ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.268C>T (p.Arg90Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003000.3(SDHB):c.268C>T (p.Arg90Ter)
Variation ID: 12778 Accession: VCV000012778.86
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17033078 (GRCh38) [ NCBI UCSC ] 1: 17359573 (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 1, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.268C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg90Ter nonsense NC_000001.11:g.17033078G>A NC_000001.10:g.17359573G>A NG_012340.1:g.26093C>T LRG_316:g.26093C>T LRG_316t1:c.268C>T LRG_316p1:p.Arg90Ter - Protein change
- R90*
- Other names
- p.R90*:CGA>TGA
- Canonical SPDI
- NC_000001.11:17033077:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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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SDHB | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1292 | 1407 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000013616.31 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 17, 2022 | RCV000037718.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000183211.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV000215883.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV000627749.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763272.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 10, 2023 | RCV003233026.8 |
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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Pathogenic
(Mar 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061380.7
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
The p.Arg90X variant in SDHB has previously been identified in at least 12 individuals with SDHB-associated tumors and segregated with disease in 9 affected family … (more)
The p.Arg90X variant in SDHB has previously been identified in at least 12 individuals with SDHB-associated tumors and segregated with disease in 9 affected family members from at least 5 families (Amar 2005, Zu 2011, Srirangalingam 2008, Benn 2006, Hensen 2012, Elston 2017, Gill 2011, Lee 2014, Crona 2014, Burnichon 2009, Benn 2003). It has also been identified in 2/113664 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 12778). This nonsense variant leads to a premature termination codon at position 90, which is predicted to lead to a truncated or absent protein. Functional studies support an impact on protein function (Kim 2015, Elston 2017). Heterozygous loss of function of the SDHB gene is an established disease mechanism in patients with hereditary paraganglioma and pheochromocytoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary paraganglioma and pheochromocytoma. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS3_Supporting. (less)
Number of individuals with the variant: 2
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Pathogenic
(May 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053299.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023 |
Comment:
Variant summary: SDHB c.268C>T (p.Arg90X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SDHB c.268C>T (p.Arg90X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes (gnomAD). c.268C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Astuti_2001, Benn_2006, Andrews_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant has no protein activity (Kim_2015). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761844.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806426.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000274572.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.R90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the SDHB gene, results from a C to T substitution at … (more)
The p.R90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the SDHB gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from an arginine to a stop codon within coding exon 3. This pathogenic mutation has been reported in multiple unrelated families exhibiting pheochromocytomas and/or paragangliomas (Astuti D et al. Am J Hum Genet. 2001 Jul;69(1):49-54; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71; Crona J et al. PLoS One. 2014 Jan;9(1):e86756; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435; Albattal S et al. Oncotarget. 2019 Oct 15;10(57):5919-5931). This mutation has also been identified in a woman with a renal tumor and family history of paragangliomas, where the renal tumor demonstrated negative SDHB staining by immunohistochemistry (Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35:1578-85). It was recently seen in a patient with a duodenal GIST who also had a family history of paragangliomas. IHC analysis of the GIST showed negative SDHB staining, and the tumor was positive for the p.R90* mutation (Elston MS et al. J. Clin. Endocrinol. Metab. 2017 May;102(5):1447-1450). In vitro data showed complete loss of SDHB expression in cytosolic and mitochondrial compartments as well as no measurable SDH activity in cells transfected with this truncating mutation (Kim E et al. Endocr. Relat. Cancer 2015 Jun;22:387-97). Of note, this mutation is referred to as p.R91X in the Astuti (2001) paper. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 21, 2014)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255462.2 First in ClinVar: Oct 11, 2015 Last updated: Jan 09, 2016 |
Age: 50-59 years
Sex: male
Ethnicity/Population group: European Caucasian
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Pheochromocytoma Carney-Stratakis syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893916.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774863.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This nonsense variant causes the premature termination of SDHB protein synthesis. In the published literature, the variant has been reported in individuals with paraganglioma, pheochromocytoma, … (more)
This nonsense variant causes the premature termination of SDHB protein synthesis. In the published literature, the variant has been reported in individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumor, and renal cell carcinoma (PMIDs: 28374168 (2017), 28324028 (2017), 23083876 (2012), 19454582 (2009), 18419787 (2008), and 11404820 (2001)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Dec 10, 2021)
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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: SCV000235630.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(R62*); This variant is associated with the following publications: (PMID: 26332594, 27573198, 17102068, 20061288, 25371406, 27171833, 16314641, 18419787, 25972245, 25525159, 22517557, 11404820, 28324028, 26230854, 21934479, 26464466, 23083876, 28374168, 19454582, 28973655, 15328326, 19576851, 12618761, 16317055, 24659481, 28748451, 30050099, 31666924, 31492822, 32804377, 32741965, 30787465, 33726816) (less)
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Pathogenic
(Aug 15, 2023)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760634.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Pathogenic
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)
Accession: SCV003930413.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Paragangliomas 4 Pheochromocytoma
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000554022.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg90*) in the SDHB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg90*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs74315366, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma, paraganglioma and renal cell carcinoma (PMID: 11404820, 12618761, 16314641, 16317055, 18419787, 19454582, 21348866, 21934479, 23083876, 24466223, 25326637). This variant is also known as R91X. ClinVar contains an entry for this variant (Variation ID: 12778). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004933588.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary pheochromocytoma-paraganglioma
Affected status: yes
Allele origin:
germline
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Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599490.1
First in ClinVar: Sep 14, 2017 Last updated: Sep 14, 2017 |
Observation 1: Observation 2: Observation 3: |
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Pathogenic
(Jul 01, 2001)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033863.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In affected members of 3 families with pheochromocytoma/paraganglioma syndrome-4 (PPGL4; 115310), Astuti et al. (2001) identified a 402C-T transition in the SDHB gene, resulting in … (more)
In affected members of 3 families with pheochromocytoma/paraganglioma syndrome-4 (PPGL4; 115310), Astuti et al. (2001) identified a 402C-T transition in the SDHB gene, resulting in an arg90-to-ter (R90X) substitution. The mutation was predicted to result in a truncated SDHB protein lacking the C-terminal 191 amino acids. One of the families had been reported by Skoldberg et al. (1998). The mutation occurred at a hypermutable CpG dinucleotide; haplotype analysis of the 3 families supported independent origin of the mutations. This mutation was originally published as ARG91TER; the corrected numbering appeared in an erratum. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. | Andrews KA | Journal of medical genetics | 2018 | PMID: 29386252 |
SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. | Jochmanova I | Journal of cancer research and clinical oncology | 2017 | PMID: 28374168 |
A Duodenal SDH-Deficient Gastrointestinal Stromal Tumor in a Patient With a Germline SDHB Mutation. | Elston MS | The Journal of clinical endocrinology and metabolism | 2017 | PMID: 28324028 |
Calculating the optimal surveillance for head and neck paraganglioma in SDHB-mutation carriers. | Eijkelenkamp K | Familial cancer | 2017 | PMID: 27573198 |
Attention Deficit Hyperactivity Disorder in Pediatric Patients with Pheochromocytoma and Paraganglioma. | Batsis M | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2016 | PMID: 27171833 |
Structural and functional consequences of succinate dehydrogenase subunit B mutations. | Kim E | Endocrine-related cancer | 2015 | PMID: 25972245 |
Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
Integrative genetic characterization and phenotype correlations in pheochromocytoma and paraganglioma tumours. | Crona J | PloS one | 2014 | PMID: 24466223 |
Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. | Ricketts CJ | The Journal of urology | 2012 | PMID: 23083876 |
High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. | Hensen EF | Clinical genetics | 2012 | PMID: 21348866 |
Renal tumors associated with germline SDHB mutation show distinctive morphology. | Gill AJ | The American journal of surgical pathology | 2011 | PMID: 21934479 |
[The mutations of germline succinate dehydrogrnase subunit B (SDHB) in sporadic paragangliomas]. | Zu TJ | Shanghai kou qiang yi xue = Shanghai journal of stomatology | 2011 | PMID: 21909610 |
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. | Burnichon N | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19454582 |
Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. | Srirangalingam U | Clinical endocrinology | 2008 | PMID: 18419787 |
Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. | Benn DE | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16317055 |
Genetic testing in pheochromocytoma or functional paraganglioma. | Amar L | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16314641 |
Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. | Benn DE | Oncogene | 2003 | PMID: 12618761 |
Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. | Astuti D | American journal of human genetics | 2001 | PMID: 11404820 |
A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes. | Sköldberg F | Clinical endocrinology | 1998 | PMID: 9509062 |
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Text-mined citations for rs74315366 ...
HelpRecord last updated Jun 02, 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.