ClinVar Genomic variation as it relates to human health
NM_033337.2(CAV3):c.216C>G (p.Cys72Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(1); Benign(6); Likely benign(10)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_033337.2(CAV3):c.216C>G (p.Cys72Trp)
Variation ID: 8279 Accession: VCV000008279.91
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 8745627 (GRCh38) [ NCBI UCSC ] 3: 8787313 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033337.3:c.216C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203123.1:p.Cys72Trp missense NM_001234.5:c.216C>G NP_001225.1:p.Cys72Trp missense NC_000003.12:g.8745627C>G NC_000003.11:g.8787313C>G NG_008797.2:g.16818C>G LRG_329:g.16818C>G LRG_329t1:c.216C>G LRG_329p1:p.Cys72Trp P56539:p.Cys72Trp - Protein change
- C72W
- Other names
- -
- Canonical SPDI
- NC_000003.12:8745626:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- unknown functional consequence
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
Exome Aggregation Consortium (ExAC) 0.00112
The Genome Aggregation Database (gnomAD), exomes 0.00137
The Genome Aggregation Database (gnomAD) 0.00164
Trans-Omics for Precision Medicine (TOPMed) 0.00183
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CAV3 | - | - |
GRCh38 GRCh37 |
100 | 440 | |
OXTR | - | - |
GRCh38 GRCh37 |
29 | 368 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2005 | RCV000008769.12 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2022 | RCV000024381.35 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Jul 13, 2020 | RCV000150236.23 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 24, 2013 | RCV000171752.10 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 7, 2018 | RCV000249612.12 | |
Uncertain significance (1) |
no assertion criteria provided
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Mar 16, 2016 | RCV000477819.10 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2019 | RCV000769171.13 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001084478.14 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jul 7, 2023 | RCV001144018.13 | |
Benign (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV000987087.10 | |
CAV3-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Nov 5, 2019 | RCV003952349.1 |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Muscular dystrophy, limb girdle
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050766.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 6
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Likely benign
(Dec 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740557.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Benign
(Jul 07, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000227543.5
First in ClinVar: Jun 28, 2015 Last updated: May 29, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Apr 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197226.4
First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 11
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Likely benign
(Mar 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995703.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Caveolinopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001304592.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Jul 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001426790.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
Comment:
Variant summary: CAV3 c.216C>G (p.Cys72Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CAV3 c.216C>G (p.Cys72Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 283742 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 230 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAV3 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.216C>G has been reported in the literature in individuals with Muscular dystrophy, Long QT syndrome, Sudden Arrhythmic Death Syndrome, Dilated cardiomyopathy or Hypertrophic cardiomyopathy (McNally_1998, Arnestad_2007, Vatta_2006, Pugh_2014, Nunn_2015, Rubattu_2016, Sanchez_2016, Minoche_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In addition, co-occurrences with other pathogenic variants have been reported (MYBPC3 c.1483C>T, p.Arg495Trp; TTN c.69491_69492del, p.Val23164fs) (Rubattu_2016, Minoche_2018), providing supporting evidence for a benign role. At least one publication reports this variant has no impact on protein function (Cai_2009). Ten ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance (3x), likely benign (5x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV000900546.3
First in ClinVar: May 06, 2019 Last updated: Jan 01, 2022 |
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Likely benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000261574.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Caveolinopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812488.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Likely benign
(Sep 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000317954.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Aug 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153761.22
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
CAV3: BS1, BS2
Number of individuals with the variant: 2
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Likely benign
(Feb 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885143.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 26, 2021 |
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Benign
(Dec 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001477112.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Benign
(Nov 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001887388.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 25630502, 31043699, 27600940, 25783436, 9536092, 23465283, 11251997)
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001136285.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Likely benign
(Nov 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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CAV3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004766774.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Pathogenic
(Jan 01, 2005)
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no assertion criteria provided
Method: literature only
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RIPPLING MUSCLE DISEASE 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028978.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
The numbering of this CAV3 mutation (C72W) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation CYS71TRP. … (more)
The numbering of this CAV3 mutation (C72W) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation CYS71TRP. In 1 of 82 patients with muscular dystrophy (see RMD2; 606072), McNally et al. (1998) identified a heterozygous C-to-G change in the CAV3 gene, resulting in a cys71-to-trp (C71W) substitution. The patient had progressive proximal muscle weakness beginning in the first decade, but remained ambulatory in the mid-second decade. Her mother and 2 siblings had the identical missense change, but did not have symptoms of muscular dystrophy, suggesting that a single abnormal allele is not sufficient to cause the phenotype and that the likely inheritance is autosomal recessive. The authors were unable to determine the nature of the second allele in the proband. The mutation was not identified in 200 control chromosomes. McNally (1998) suspected that the phenotype was the result of either loss-of-function mutations or dominant-negative mutations; she doubted that haploinsufficiency leads to the disease. The family was lost to follow-up. Among 100 normal Brazilian control subjects, de Paula et al. (2001) identified heterozygosity for the C71W change in 1 subject. They concluded that C71W is a rare polymorphism that does not cause an abnormal phenotype when present in just one allele. (less)
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Uncertain significance
(Mar 16, 2016)
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no assertion criteria provided
Method: research
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Rippling muscle disease 2
Hypertrophic cardiomyopathy 1 Elevated circulating creatine kinase concentration Long QT syndrome 9 Rippling muscle disease 2 Distal myopathy, Tateyama type
Affected status: yes
Allele origin:
paternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536872.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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not provided
(Apr 15, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (CAV3)
Accession: SCV000045674.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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unknown functional consequence
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Leiden Muscular Dystrophy (CAV3)
Accession: SCV000045674.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy. | Minoche AE | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29961767 |
Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. | Sanchez O | PloS one | 2016 | PMID: 27930701 |
A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort. | Rubattu S | International journal of molecular sciences | 2016 | PMID: 27483260 |
Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing. | Nunn LM | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2016 | PMID: 26498160 |
CAV3 gene sequence variations: National Genome Database and clinics. | Stavusis J | Acta neurologica Scandinavica | 2015 | PMID: 25630502 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data. | Andreasen C | The Canadian journal of cardiology | 2013 | PMID: 23465283 |
Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3, and dysferlin. | Cai C | The Journal of biological chemistry | 2009 | PMID: 19380584 |
Expression of the muscular dystrophy-associated caveolin-3(P104L) mutant in adult mouse skeletal muscle specifically alters the Ca(2+) channel function of the dihydropyridine receptor. | Weiss N | Pflugers Archiv : European journal of physiology | 2008 | PMID: 18509671 |
Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. | Arnestad M | Circulation | 2007 | PMID: 17210839 |
Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. | Vatta M | Circulation | 2006 | PMID: 17060380 |
Molecular and muscle pathology in a series of caveolinopathy patients. | Fulizio L | Human mutation | 2005 | PMID: 15580566 |
Inhibition of lipid raft-dependent signaling by a dystrophy-associated mutant of caveolin-3. | Carozzi AJ | The Journal of biological chemistry | 2002 | PMID: 11884389 |
Mutations in the caveolin-3 gene: When are they pathogenic? | de Paula F | American journal of medical genetics | 2001 | PMID: 11251997 |
Caveolin-3 in muscular dystrophy. | McNally EM | Human molecular genetics | 1998 | PMID: 9536092 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAV3 | - | - | - | - |
McNally, E. M. Personal Communication. 1998. Chicago, Ill. | - | - | - | - |
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Text-mined citations for rs116840776 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.