VCV000821031.13 - ClinVar

NM_020975.6(RET):c.2286G>C (p.Glu762Asp)

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.

(4)

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.2286G>C (p.Glu762Asp)

Variation ID: 821031 Accession: VCV000821031.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43118374 (GRCh38) [ NCBI UCSC ] 10: 43613822 (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 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.2286G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Glu762Asp	missense
NM_000323.2:c.2286G>C	NP_000314.1:p.Glu762Asp	missense
NM_001355216.2:c.1524G>C	NP_001342145.1:p.Glu508Asp	missense
NM_001406743.1:c.2286G>C	NP_001393672.1:p.Glu762Asp	missense
NM_001406744.1:c.2286G>C	NP_001393673.1:p.Glu762Asp	missense
NM_001406759.1:c.2286G>C	NP_001393688.1:p.Glu762Asp	missense
NM_001406760.1:c.2286G>C	NP_001393689.1:p.Glu762Asp	missense
NM_001406761.1:c.2157G>C	NP_001393690.1:p.Glu719Asp	missense
NM_001406762.1:c.2157G>C	NP_001393691.1:p.Glu719Asp	missense
NM_001406763.1:c.2151G>C	NP_001393692.1:p.Glu717Asp	missense
NM_001406764.1:c.2157G>C	NP_001393693.1:p.Glu719Asp	missense
NM_001406765.1:c.2151G>C	NP_001393694.1:p.Glu717Asp	missense
NM_001406766.1:c.1998G>C	NP_001393695.1:p.Glu666Asp	missense
NM_001406767.1:c.1998G>C	NP_001393696.1:p.Glu666Asp	missense
NM_001406768.1:c.2022G>C	NP_001393697.1:p.Glu674Asp	missense
NM_001406769.1:c.1890G>C	NP_001393698.1:p.Glu630Asp	missense
NM_001406770.1:c.1998G>C	NP_001393699.1:p.Glu666Asp	missense
NM_001406771.1:c.1848G>C	NP_001393700.1:p.Glu616Asp	missense
NM_001406772.1:c.1890G>C	NP_001393701.1:p.Glu630Asp	missense
NM_001406773.1:c.1848G>C	NP_001393702.1:p.Glu616Asp	missense
NM_001406774.1:c.1761G>C	NP_001393703.1:p.Glu587Asp	missense
NM_001406775.1:c.1560G>C	NP_001393704.1:p.Glu520Asp	missense
NM_001406776.1:c.1560G>C	NP_001393705.1:p.Glu520Asp	missense
NM_001406777.1:c.1560G>C	NP_001393706.1:p.Glu520Asp	missense
NM_001406778.1:c.1560G>C	NP_001393707.1:p.Glu520Asp	missense
NM_001406779.1:c.1389G>C	NP_001393708.1:p.Glu463Asp	missense
NM_001406780.1:c.1389G>C	NP_001393709.1:p.Glu463Asp	missense
NM_001406781.1:c.1389G>C	NP_001393710.1:p.Glu463Asp	missense
NM_001406782.1:c.1389G>C	NP_001393711.1:p.Glu463Asp	missense
NM_001406783.1:c.1260G>C	NP_001393712.1:p.Glu420Asp	missense
NM_001406784.1:c.1296G>C	NP_001393713.1:p.Glu432Asp	missense
NM_001406785.1:c.1269G>C	NP_001393714.1:p.Glu423Asp	missense
NM_001406786.1:c.1260G>C	NP_001393715.1:p.Glu420Asp	missense
NM_001406787.1:c.1254G>C	NP_001393716.1:p.Glu418Asp	missense
NM_001406788.1:c.1101G>C	NP_001393717.1:p.Glu367Asp	missense
NM_001406789.1:c.1101G>C	NP_001393718.1:p.Glu367Asp	missense
NM_001406790.1:c.1101G>C	NP_001393719.1:p.Glu367Asp	missense
NM_001406791.1:c.981G>C	NP_001393720.1:p.Glu327Asp	missense
NM_001406792.1:c.837G>C	NP_001393721.1:p.Glu279Asp	missense
NM_001406793.1:c.837G>C	NP_001393722.1:p.Glu279Asp	missense
NM_001406794.1:c.837G>C	NP_001393723.1:p.Glu279Asp	missense
NM_020629.2:c.2286G>C	NP_065680.1:p.Glu762Asp	missense
NM_020630.7:c.2286G>C	NP_065681.1:p.Glu762Asp	missense
NC_000010.11:g.43118374G>C
NC_000010.10:g.43613822G>C
NG_007489.1:g.46306G>C
LRG_518:g.46306G>C
LRG_518t1:c.2286G>C	LRG_518p1:p.Glu762Asp
LRG_518t2:c.2286G>C	LRG_518p2:p.Glu762Asp

... more HGVS ... less HGVS

Protein change

E762D, E508D, E418D, E420D, E520D, E327D, E423D, E587D, E666D, E279D, E367D, E463D, E630D, E674D, E717D, E432D, E616D, E719D

Other names

Canonical SPDI

NC_000010.11:43118373:G:C

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 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1323183090 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	3594	3716

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.
Multiple endocrine neoplasia, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 27, 2023	RCV001054004.10
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 5, 2023	RCV001015065.4
Familial medullary thyroid carcinoma Hirschsprung disease, susceptibility to, 1 Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B Pheochromocytoma	Uncertain significance (1)	criteria provided, single submitter	Jul 9, 2021	RCV002481824.1

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 (Jul 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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	Fulgent Genetics, Fulgent Genetics Accession: SCV002779937.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 05, 2023)	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: SCV001175858.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.E762D variant (also known as c.2286G>C), located in coding exon 13 of the RET gene, results from a G to C substitution at nucleotide … (more) The p.E762D variant (also known as c.2286G>C), located in coding exon 13 of the RET gene, results from a G to C substitution at nucleotide position 2286. The glutamic acid at codon 762 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain Significance (Nov 30, 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: SCV004832149.1 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 glutamic acid with aspartic acid at codon 762 of the RET protein. Computational prediction is inconclusive regarding the impact of this … (more) This missense variant replaces glutamic acid with aspartic acid at codon 762 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 2/250954 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: 2
Uncertain significance (Dec 27, 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: SCV001218295.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 762 of the RET … (more) This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 762 of the RET protein (p.Glu762Asp). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 821031). 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 tolerated. 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)

Comment:

The p.E762D variant (also known as c.2286G>C), located in coding exon 13 of the RET gene, results from a G to C substitution at nucleotide position 2286. The glutamic acid at codon 762 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces glutamic acid with aspartic acid at codon 762 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 2/250954 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:

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 762 of the RET protein (p.Glu762Asp). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 821031). 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 tolerated. 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 rs1323183090 ...

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.2286G>C (p.Glu762Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1323183090 ...