ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.134C>T (p.Ala45Val)
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_020975.6(RET):c.134C>T (p.Ala45Val)
Variation ID: 405538 Accession: VCV000405538.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43100519 (GRCh38) [ NCBI UCSC ] 10: 43595967 (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 May 22, 2017 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.134C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Ala45Val missense NM_000323.2:c.134C>T NP_000314.1:p.Ala45Val missense NM_001406743.1:c.134C>T NP_001393672.1:p.Ala45Val missense NM_001406744.1:c.134C>T NP_001393673.1:p.Ala45Val missense NM_001406759.1:c.134C>T NP_001393688.1:p.Ala45Val missense NM_001406760.1:c.134C>T NP_001393689.1:p.Ala45Val missense NM_001406761.1:c.134C>T NP_001393690.1:p.Ala45Val missense NM_001406762.1:c.134C>T NP_001393691.1:p.Ala45Val missense NM_001406763.1:c.134C>T NP_001393692.1:p.Ala45Val missense NM_001406764.1:c.134C>T NP_001393693.1:p.Ala45Val missense NM_001406765.1:c.134C>T NP_001393694.1:p.Ala45Val missense NM_001406766.1:c.134C>T NP_001393695.1:p.Ala45Val missense NM_001406767.1:c.134C>T NP_001393696.1:p.Ala45Val missense NM_001406768.1:c.134C>T NP_001393697.1:p.Ala45Val missense NM_001406769.1:c.134C>T NP_001393698.1:p.Ala45Val missense NM_001406770.1:c.134C>T NP_001393699.1:p.Ala45Val missense NM_001406771.1:c.134C>T NP_001393700.1:p.Ala45Val missense NM_001406772.1:c.134C>T NP_001393701.1:p.Ala45Val missense NM_001406773.1:c.134C>T NP_001393702.1:p.Ala45Val missense NM_001406774.1:c.134C>T NP_001393703.1:p.Ala45Val missense NM_001406775.1:c.134C>T NP_001393704.1:p.Ala45Val missense NM_001406776.1:c.134C>T NP_001393705.1:p.Ala45Val missense NM_001406777.1:c.134C>T NP_001393706.1:p.Ala45Val missense NM_001406778.1:c.134C>T NP_001393707.1:p.Ala45Val missense NM_001406779.1:c.134C>T NP_001393708.1:p.Ala45Val missense NM_001406780.1:c.134C>T NP_001393709.1:p.Ala45Val missense NM_001406781.1:c.134C>T NP_001393710.1:p.Ala45Val missense NM_001406782.1:c.134C>T NP_001393711.1:p.Ala45Val missense NM_001406783.1:c.134C>T NP_001393712.1:p.Ala45Val missense NM_001406785.1:c.134C>T NP_001393714.1:p.Ala45Val missense NM_001406786.1:c.134C>T NP_001393715.1:p.Ala45Val missense NM_001406787.1:c.134C>T NP_001393716.1:p.Ala45Val missense NM_001406788.1:c.134C>T NP_001393717.1:p.Ala45Val missense NM_001406789.1:c.134C>T NP_001393718.1:p.Ala45Val missense NM_001406790.1:c.134C>T NP_001393719.1:p.Ala45Val missense NM_001406791.1:c.134C>T NP_001393720.1:p.Ala45Val missense NM_020629.2:c.134C>T NP_065680.1:p.Ala45Val missense NM_020630.7:c.134C>T NP_065681.1:p.Ala45Val missense NM_020975.4:c.134_135delinsTG NC_000010.11:g.43100519C>T NC_000010.10:g.43595967C>T NG_007489.1:g.28451C>T LRG_518:g.28451C>T LRG_518t1:c.134C>T LRG_518p1:p.Ala45Val LRG_518t2:c.134C>T LRG_518p2:p.Ala45Val - Protein change
- A45V
- Other names
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- Canonical SPDI
- NC_000010.11:43100518:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3523 | 3643 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2020 | RCV000489446.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 16, 2021 | RCV000568194.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 2, 2018 | RCV000662783.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2023 | RCV001821237.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 29, 2023 | RCV003463861.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV004000673.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 6, 2021 | RCV002481388.8 |
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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Uncertain significance
(Sep 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785592.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Aug 01, 2018)
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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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GeneKor MSA
Accession: SCV000822189.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Aug 28, 2020)
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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: SCV000577198.5
First in ClinVar: May 22, 2017 Last updated: Sep 24, 2021 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 28350084) (less)
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Uncertain significance
(Mar 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002068662.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838365.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Nov 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Familial medullary thyroid carcinoma Multiple endocrine neoplasia type 2B Pheochromocytoma Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002776426.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jan 16, 2023)
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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: SCV003801162.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: RET c.134_135delinsTG (p.Ala45Val) results in a non-conservative amino acid change located in the RET Cadherin like domain 1 (IPR041163) of the encoded protein … (more)
Variant summary: RET c.134_135delinsTG (p.Ala45Val) results in a non-conservative amino acid change located in the RET Cadherin like domain 1 (IPR041163) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249804 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134_135delinsTG has been reported in the literature in an individual referred for genetic testing with a hereditary cancer panel (Tsaousis_2019). This report does not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, a different variant resulting in the same amino acid change (c.134C>T, p.Ala45Val) has been cited in ClinVar as a variant of uncertain significance by eight submitters (evaluation after 2014). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208697.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jul 16, 2021)
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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: SCV000664523.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.A45V variant (also known as c.134C>T), located in coding exon 2 of the RET gene, results from a C to T substitution at nucleotide … (more)
The p.A45V variant (also known as c.134C>T), located in coding exon 2 of the RET gene, results from a C to T substitution at nucleotide position 134. The alanine at codon 45 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004838624.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces alanine with valine at codon 45 of the RET protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with valine at codon 45 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/249804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 4
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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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Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Text-mined citations for rs763526874 ...
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.