VCV000818716.8 - ClinVar

NM_020975.6(RET):c.129C>A (p.Asp43Glu)

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.

(3)

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.129C>A (p.Asp43Glu)

Variation ID: 818716 Accession: VCV000818716.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43100514 (GRCh38) [ NCBI UCSC ] 10: 43595962 (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	Mar 16, 2020	May 1, 2024	Dec 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.129C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Asp43Glu	missense
NM_000323.2:c.129C>A	NP_000314.1:p.Asp43Glu	missense
NM_001406743.1:c.129C>A	NP_001393672.1:p.Asp43Glu	missense
NM_001406744.1:c.129C>A	NP_001393673.1:p.Asp43Glu	missense
NM_001406759.1:c.129C>A	NP_001393688.1:p.Asp43Glu	missense
NM_001406760.1:c.129C>A	NP_001393689.1:p.Asp43Glu	missense
NM_001406761.1:c.129C>A	NP_001393690.1:p.Asp43Glu	missense
NM_001406762.1:c.129C>A	NP_001393691.1:p.Asp43Glu	missense
NM_001406763.1:c.129C>A	NP_001393692.1:p.Asp43Glu	missense
NM_001406764.1:c.129C>A	NP_001393693.1:p.Asp43Glu	missense
NM_001406765.1:c.129C>A	NP_001393694.1:p.Asp43Glu	missense
NM_001406766.1:c.129C>A	NP_001393695.1:p.Asp43Glu	missense
NM_001406767.1:c.129C>A	NP_001393696.1:p.Asp43Glu	missense
NM_001406768.1:c.129C>A	NP_001393697.1:p.Asp43Glu	missense
NM_001406769.1:c.129C>A	NP_001393698.1:p.Asp43Glu	missense
NM_001406770.1:c.129C>A	NP_001393699.1:p.Asp43Glu	missense
NM_001406771.1:c.129C>A	NP_001393700.1:p.Asp43Glu	missense
NM_001406772.1:c.129C>A	NP_001393701.1:p.Asp43Glu	missense
NM_001406773.1:c.129C>A	NP_001393702.1:p.Asp43Glu	missense
NM_001406774.1:c.129C>A	NP_001393703.1:p.Asp43Glu	missense
NM_001406775.1:c.129C>A	NP_001393704.1:p.Asp43Glu	missense
NM_001406776.1:c.129C>A	NP_001393705.1:p.Asp43Glu	missense
NM_001406777.1:c.129C>A	NP_001393706.1:p.Asp43Glu	missense
NM_001406778.1:c.129C>A	NP_001393707.1:p.Asp43Glu	missense
NM_001406779.1:c.129C>A	NP_001393708.1:p.Asp43Glu	missense
NM_001406780.1:c.129C>A	NP_001393709.1:p.Asp43Glu	missense
NM_001406781.1:c.129C>A	NP_001393710.1:p.Asp43Glu	missense
NM_001406782.1:c.129C>A	NP_001393711.1:p.Asp43Glu	missense
NM_001406783.1:c.129C>A	NP_001393712.1:p.Asp43Glu	missense
NM_001406785.1:c.129C>A	NP_001393714.1:p.Asp43Glu	missense
NM_001406786.1:c.129C>A	NP_001393715.1:p.Asp43Glu	missense
NM_001406787.1:c.129C>A	NP_001393716.1:p.Asp43Glu	missense
NM_001406788.1:c.129C>A	NP_001393717.1:p.Asp43Glu	missense
NM_001406789.1:c.129C>A	NP_001393718.1:p.Asp43Glu	missense
NM_001406790.1:c.129C>A	NP_001393719.1:p.Asp43Glu	missense
NM_001406791.1:c.129C>A	NP_001393720.1:p.Asp43Glu	missense
NM_020629.2:c.129C>A	NP_065680.1:p.Asp43Glu	missense
NM_020630.7:c.129C>A	NP_065681.1:p.Asp43Glu	missense
NC_000010.11:g.43100514C>A
NC_000010.10:g.43595962C>A
NG_007489.1:g.28446C>A
LRG_518:g.28446C>A
LRG_518t1:c.129C>A	LRG_518p1:p.Asp43Glu
LRG_518t2:c.129C>A	LRG_518p2:p.Asp43Glu

... more HGVS ... less HGVS

Protein change

D43E

Other names

Canonical SPDI

NC_000010.11:43100513:C:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1488040686 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	3598	3720

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	Aug 11, 2022	RCV001010592.5
Multiple endocrine neoplasia, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 5, 2023	RCV003532346.4

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 (Aug 11, 2022)	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: SCV001170816.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.D43E variant (also known as c.129C>A), located in coding exon 2 of the RET gene, results from a C to A substitution at nucleotide … (more) The p.D43E variant (also known as c.129C>A), located in coding exon 2 of the RET gene, results from a C to A substitution at nucleotide position 129. The aspartic acid at codon 43 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is 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 variant remains unclear. (less)
Uncertain significance (Dec 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple endocrine neoplasia, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004265908.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 43 of the RET … (more) This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 43 of the RET protein (p.Asp43Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 818716). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (May 31, 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: SCV004828131.1 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)	Number of individuals with the variant: 1

Comment:

The p.D43E variant (also known as c.129C>A), located in coding exon 2 of the RET gene, results from a C to A substitution at nucleotide position 129. The aspartic acid at codon 43 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is 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 variant remains unclear.

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 43 of the RET protein (p.Asp43Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 818716). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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 rs1488040686 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.129C>A (p.Asp43Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1488040686 ...