VCV001769192.6 - ClinVar

NM_020975.6(RET):c.1295C>T (p.Ala432Val)

Germline

Classification

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.1295C>T (p.Ala432Val)

Variation ID: 1769192 Accession: VCV001769192.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43111238 (GRCh38) [ NCBI UCSC ] 10: 43606686 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 29, 2022	Oct 8, 2024	Mar 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.1295C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Ala432Val	missense
NM_000323.2:c.1295C>T	NP_000314.1:p.Ala432Val	missense
NM_001355216.2:c.533C>T	NP_001342145.1:p.Ala178Val	missense
NM_001406743.1:c.1295C>T	NP_001393672.1:p.Ala432Val	missense
NM_001406744.1:c.1295C>T	NP_001393673.1:p.Ala432Val	missense
NM_001406759.1:c.1295C>T	NP_001393688.1:p.Ala432Val	missense
NM_001406760.1:c.1295C>T	NP_001393689.1:p.Ala432Val	missense
NM_001406761.1:c.1166C>T	NP_001393690.1:p.Ala389Val	missense
NM_001406762.1:c.1166C>T	NP_001393691.1:p.Ala389Val	missense
NM_001406763.1:c.1295C>T	NP_001393692.1:p.Ala432Val	missense
NM_001406764.1:c.1166C>T	NP_001393693.1:p.Ala389Val	missense
NM_001406765.1:c.1295C>T	NP_001393694.1:p.Ala432Val	missense
NM_001406766.1:c.1007C>T	NP_001393695.1:p.Ala336Val	missense
NM_001406767.1:c.1007C>T	NP_001393696.1:p.Ala336Val	missense
NM_001406768.1:c.1166C>T	NP_001393697.1:p.Ala389Val	missense
NM_001406769.1:c.899C>T	NP_001393698.1:p.Ala300Val	missense
NM_001406770.1:c.1007C>T	NP_001393699.1:p.Ala336Val	missense
NM_001406771.1:c.857C>T	NP_001393700.1:p.Ala286Val	missense
NM_001406772.1:c.899C>T	NP_001393701.1:p.Ala300Val	missense
NM_001406773.1:c.857C>T	NP_001393702.1:p.Ala286Val	missense
NM_001406774.1:c.770C>T	NP_001393703.1:p.Ala257Val	missense
NM_001406775.1:c.569C>T	NP_001393704.1:p.Ala190Val	missense
NM_001406776.1:c.569C>T	NP_001393705.1:p.Ala190Val	missense
NM_001406777.1:c.569C>T	NP_001393706.1:p.Ala190Val	missense
NM_001406778.1:c.569C>T	NP_001393707.1:p.Ala190Val	missense
NM_001406784.1:c.305C>T	NP_001393713.1:p.Ala102Val	missense
NM_020629.2:c.1295C>T	NP_065680.1:p.Ala432Val	missense
NM_020630.5:c.1295C>T
NM_020630.7:c.1295C>T	NP_065681.1:p.Ala432Val	missense
NC_000010.11:g.43111238C>T
NC_000010.10:g.43606686C>T
NG_007489.1:g.39170C>T
LRG_518:g.39170C>T
LRG_518t1:c.1295C>T	LRG_518p1:p.Ala432Val
LRG_518t2:c.1295C>T	LRG_518p2:p.Ala432Val

... more HGVS ... less HGVS

Protein change

A102V, A300V, A257V, A178V, A190V, A336V, A286V, A389V, A432V

Other names

Canonical SPDI

NC_000010.11:43111237:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

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
Gene	OMIM	HI score Help 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.
RET		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3593	3715

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Mar 12, 2024	RCV002380630.2
Multiple endocrine neoplasia type 2A	Uncertain significance (1)	criteria provided, single submitter	Nov 28, 2023	RCV003444270.1
Multiple endocrine neoplasia, type 2	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV004007298.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Feb 16, 2024	RCV004725265.1
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Nov 29, 2023	RCV004572400.1

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.
Uncertain significance (Nov 28, 2023)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV004171434.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Comment: The RET c.1295C>T (p.Ala432Val) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more) The RET c.1295C>T (p.Ala432Val) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
Uncertain Significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia, type 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004833066.1 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)	Comment: This missense variant replaces alanine with valine at codon 432 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 432 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 variant in individuals affected with RET-related disorders in the literature. This variant has been identified in 5/282564 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: 3
Uncertain significance (Mar 12, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002690930.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.A432V variant (also known as c.1295C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide … (more) The p.A432V variant (also known as c.1295C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1295. The alanine at codon 432 is replaced by valine, an amino acid with similar properties. This amino acid position is not well 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)
Uncertain significance (Nov 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054227.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Feb 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005331649.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923) (less)

Comment:

The RET c.1295C>T (p.Ala432Val) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Comment:

This missense variant replaces alanine with valine at codon 432 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 variant in individuals affected with RET-related disorders in the literature. This variant has been identified in 5/282564 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.

Comment:

The p.A432V variant (also known as c.1295C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1295. The alanine at codon 432 is replaced by valine, an amino acid with similar properties. This amino acid position is not well 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.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)

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.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.1295C>T (p.Ala432Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...