VCV000024929.17 - ClinVar

NM_020975.6(RET):c.1947G>A (p.Ser649=)

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.

(6)

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.

Pathogenic/Likely pathogenic

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.1947G>A (p.Ser649=)

Variation ID: 24929 Accession: VCV000024929.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43114547 (GRCh38) [ NCBI UCSC ] 10: 43609995 (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	Apr 4, 2013	Sep 16, 2024	Jun 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.1947G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Ser649=	synonymous
NM_000323.2:c.1947G>A	NP_000314.1:p.Ser649=	synonymous
NM_001355216.2:c.1185G>A	NP_001342145.1:p.Ser395=	synonymous
NM_001406743.1:c.1947G>A	NP_001393672.1:p.Ser649=	synonymous
NM_001406744.1:c.1947G>A	NP_001393673.1:p.Ser649=	synonymous
NM_001406759.1:c.1947G>A	NP_001393688.1:p.Ser649=	synonymous
NM_001406760.1:c.1947G>A	NP_001393689.1:p.Ser649=	synonymous
NM_001406761.1:c.1818G>A	NP_001393690.1:p.Ser606=	synonymous
NM_001406762.1:c.1818G>A	NP_001393691.1:p.Ser606=	synonymous
NM_001406763.1:c.1880-68G>A		intron variant
NM_001406764.1:c.1818G>A	NP_001393693.1:p.Ser606=	synonymous
NM_001406765.1:c.1880-68G>A		intron variant
NM_001406766.1:c.1659G>A	NP_001393695.1:p.Ser553=	synonymous
NM_001406767.1:c.1659G>A	NP_001393696.1:p.Ser553=	synonymous
NM_001406768.1:c.1751-68G>A		intron variant
NM_001406769.1:c.1551G>A	NP_001393698.1:p.Ser517=	synonymous
NM_001406770.1:c.1659G>A	NP_001393699.1:p.Ser553=	synonymous
NM_001406771.1:c.1509G>A	NP_001393700.1:p.Ser503=	synonymous
NM_001406772.1:c.1551G>A	NP_001393701.1:p.Ser517=	synonymous
NM_001406773.1:c.1509G>A	NP_001393702.1:p.Ser503=	synonymous
NM_001406774.1:c.1422G>A	NP_001393703.1:p.Ser474=	synonymous
NM_001406775.1:c.1221G>A	NP_001393704.1:p.Ser407=	synonymous
NM_001406776.1:c.1221G>A	NP_001393705.1:p.Ser407=	synonymous
NM_001406777.1:c.1221G>A	NP_001393706.1:p.Ser407=	synonymous
NM_001406778.1:c.1221G>A	NP_001393707.1:p.Ser407=	synonymous
NM_001406779.1:c.1050G>A	NP_001393708.1:p.Ser350=	synonymous
NM_001406780.1:c.1050G>A	NP_001393709.1:p.Ser350=	synonymous
NM_001406781.1:c.1050G>A	NP_001393710.1:p.Ser350=	synonymous
NM_001406782.1:c.1050G>A	NP_001393711.1:p.Ser350=	synonymous
NM_001406783.1:c.921G>A	NP_001393712.1:p.Ser307=	synonymous
NM_001406784.1:c.957G>A	NP_001393713.1:p.Ser319=	synonymous
NM_001406785.1:c.930G>A	NP_001393714.1:p.Ser310=	synonymous
NM_001406786.1:c.921G>A	NP_001393715.1:p.Ser307=	synonymous
NM_001406787.1:c.983-68G>A		intron variant
NM_001406788.1:c.762G>A	NP_001393717.1:p.Ser254=	synonymous
NM_001406789.1:c.762G>A	NP_001393718.1:p.Ser254=	synonymous
NM_001406790.1:c.762G>A	NP_001393719.1:p.Ser254=	synonymous
NM_001406791.1:c.642G>A	NP_001393720.1:p.Ser214=	synonymous
NM_001406792.1:c.498G>A	NP_001393721.1:p.Ser166=	synonymous
NM_001406793.1:c.498G>A	NP_001393722.1:p.Ser166=	synonymous
NM_001406794.1:c.498G>A	NP_001393723.1:p.Ser166=	synonymous
NM_020629.2:c.1947G>A	NP_065680.1:p.Ser649=	synonymous
NM_020630.7:c.1947G>A	NP_065681.1:p.Ser649=	synonymous
NC_000010.11:g.43114547G>A
NC_000010.10:g.43609995G>A
NG_007489.1:g.42479G>A
LRG_518:g.42479G>A
LRG_518t1:c.1947G>A	LRG_518p1:p.Ser649=
LRG_518t2:c.1947G>A	LRG_518p2:p.Ser649=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:43114546:G: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.

Links

ClinGen: CA008487 dbSNP: rs377767412 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.
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 24, 2024	RCV000498649.13
Congenital central hypoventilation Familial medullary thyroid carcinoma Hirschsprung disease, susceptibility to, 1 Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B Pheochromocytoma	Likely pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762808.10
Multiple endocrine neoplasia, type 2	Likely pathogenic (1)	criteria provided, single submitter	Dec 1, 2023	RCV000821103.13
Hirschsprung disease, susceptibility to, 1	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2022	RCV001353180.11
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jun 16, 2022	RCV002408474.9

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.
Likely pathogenic (Oct 31, 2018)	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 Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893159.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hirschsprung disease, susceptibility to, 1 Affected status: yes Allele origin: inherited	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV001548341.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: ACMG codes:PS4, PS3, PM2, PP5 Number of individuals with the variant: 1 Clinical Features: Aganglionic megacolon (present)
Likely pathogenic (Feb 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: yes Allele origin: maternal	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002515373.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Publications: PubMed (1) PubMed: 36474027 Number of individuals with the variant: 1
Likely pathogenic (Dec 01, 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: SCV000961846.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 10618407‚ 21712996 Comment: This sequence change affects codon 649 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 649 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hirschsprung disease (PMID: 10618407, 21712996). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24929). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (Jun 16, 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: SCV002720887.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 10090908‚ 10618407‚ 8896569 Comment: The c.1947G>A variant (also known as p.S649S), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide … (more) The c.1947G>A variant (also known as p.S649S), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1947. This nucleotide substitution does not change the serine at codon 649. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. This alteration has been reported in multiple families affected with Hirschprung disease in the literature (Salomon R et al. Nat Genet, 1996 Nov;14:345-7; Auricchio A et al. Am J Hum Genet, 1999 Apr;64:1216-21; Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Bolk et al. performed RT-PCR analysis on RNA from a lymphoblastoid line demonstrating that the alteration creates a novel splice acceptor site within RET and partial novel splice site usage results in the deletion of first 23 amino acids of exon 11. Authors concluded that based on partial usage of the novel splice acceptor site, the S649S mutation is a hypomorphic allele (Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Based on the supporting evidence, this alteration is likely pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown. (less)
Pathogenic (Jun 24, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589353.7 First in ClinVar: Aug 20, 2017 Last updated: Sep 16, 2024	Comment: RNA studies demonstrate a damaging effect: a partial splice defect leading to an in-frame loss of 23 residues and a predicted hypomorphic allele (PMID: 10618407); … (more) RNA studies demonstrate a damaging effect: a partial splice defect leading to an in-frame loss of 23 residues and a predicted hypomorphic allele (PMID: 10618407); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16448984, 10090908, 11955539, 21712996, 8896569, 10618407, 36474027, 14633923) (less)

Comment:

This sequence change affects codon 649 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hirschsprung disease (PMID: 10618407, 21712996). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24929). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The c.1947G>A variant (also known as p.S649S), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1947. This nucleotide substitution does not change the serine at codon 649. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. This alteration has been reported in multiple families affected with Hirschprung disease in the literature (Salomon R et al. Nat Genet, 1996 Nov;14:345-7; Auricchio A et al. Am J Hum Genet, 1999 Apr;64:1216-21; Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Bolk et al. performed RT-PCR analysis on RNA from a lymphoblastoid line demonstrating that the alteration creates a novel splice acceptor site within RET and partial novel splice site usage results in the deletion of first 23 amino acids of exon 11. Authors concluded that based on partial usage of the novel splice acceptor site, the S649S mutation is a hypomorphic allele (Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Based on the supporting evidence, this alteration is likely pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown.

Comment:

RNA studies demonstrate a damaging effect: a partial splice defect leading to an in-frame loss of 23 residues and a predicted hypomorphic allele (PMID: 10618407); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16448984, 10090908, 11955539, 21712996, 8896569, 10618407, 36474027, 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

Title	Author	Journal	Year	Link
High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.	Belanger Deloge R	European journal of human genetics : EJHG	2023	PMID: 36474027
Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease.	Jiang Q	PloS one	2011	PMID: 21712996
A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus.	Bolk S	Proceedings of the National Academy of Sciences of the United States of America	2000	PMID: 10618407
Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease.	Auricchio A	American journal of human genetics	1999	PMID: 10090908
Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease.	Salomon R	Nature genetics	1996	PMID: 8896569

Text-mined citations for rs377767412 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.1947G>A (p.Ser649=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377767412 ...