VCV000024950.18 - ClinVar

NM_020975.6(RET):c.2530C>T (p.Arg844Trp)

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.

(7)

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.2530C>T (p.Arg844Trp)

Variation ID: 24950 Accession: VCV000024950.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43119668 (GRCh38) [ NCBI UCSC ] 10: 43615116 (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	Jun 17, 2024	Feb 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.2530C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Arg844Trp	missense
NM_000323.2:c.2530C>T	NP_000314.1:p.Arg844Trp	missense
NM_001355216.2:c.1768C>T	NP_001342145.1:p.Arg590Trp	missense
NM_001406743.1:c.2530C>T	NP_001393672.1:p.Arg844Trp	missense
NM_001406744.1:c.2530C>T	NP_001393673.1:p.Arg844Trp	missense
NM_001406759.1:c.2530C>T	NP_001393688.1:p.Arg844Trp	missense
NM_001406760.1:c.2530C>T	NP_001393689.1:p.Arg844Trp	missense
NM_001406761.1:c.2401C>T	NP_001393690.1:p.Arg801Trp	missense
NM_001406762.1:c.2401C>T	NP_001393691.1:p.Arg801Trp	missense
NM_001406763.1:c.2395C>T	NP_001393692.1:p.Arg799Trp	missense
NM_001406764.1:c.2401C>T	NP_001393693.1:p.Arg801Trp	missense
NM_001406765.1:c.2395C>T	NP_001393694.1:p.Arg799Trp	missense
NM_001406766.1:c.2242C>T	NP_001393695.1:p.Arg748Trp	missense
NM_001406767.1:c.2242C>T	NP_001393696.1:p.Arg748Trp	missense
NM_001406768.1:c.2266C>T	NP_001393697.1:p.Arg756Trp	missense
NM_001406769.1:c.2134C>T	NP_001393698.1:p.Arg712Trp	missense
NM_001406770.1:c.2242C>T	NP_001393699.1:p.Arg748Trp	missense
NM_001406771.1:c.2092C>T	NP_001393700.1:p.Arg698Trp	missense
NM_001406772.1:c.2134C>T	NP_001393701.1:p.Arg712Trp	missense
NM_001406773.1:c.2092C>T	NP_001393702.1:p.Arg698Trp	missense
NM_001406774.1:c.2005C>T	NP_001393703.1:p.Arg669Trp	missense
NM_001406775.1:c.1804C>T	NP_001393704.1:p.Arg602Trp	missense
NM_001406776.1:c.1804C>T	NP_001393705.1:p.Arg602Trp	missense
NM_001406777.1:c.1804C>T	NP_001393706.1:p.Arg602Trp	missense
NM_001406778.1:c.1804C>T	NP_001393707.1:p.Arg602Trp	missense
NM_001406779.1:c.1633C>T	NP_001393708.1:p.Arg545Trp	missense
NM_001406780.1:c.1633C>T	NP_001393709.1:p.Arg545Trp	missense
NM_001406781.1:c.1633C>T	NP_001393710.1:p.Arg545Trp	missense
NM_001406782.1:c.1633C>T	NP_001393711.1:p.Arg545Trp	missense
NM_001406783.1:c.1504C>T	NP_001393712.1:p.Arg502Trp	missense
NM_001406784.1:c.1540C>T	NP_001393713.1:p.Arg514Trp	missense
NM_001406785.1:c.1513C>T	NP_001393714.1:p.Arg505Trp	missense
NM_001406786.1:c.1504C>T	NP_001393715.1:p.Arg502Trp	missense
NM_001406787.1:c.1498C>T	NP_001393716.1:p.Arg500Trp	missense
NM_001406788.1:c.1345C>T	NP_001393717.1:p.Arg449Trp	missense
NM_001406789.1:c.1345C>T	NP_001393718.1:p.Arg449Trp	missense
NM_001406790.1:c.1345C>T	NP_001393719.1:p.Arg449Trp	missense
NM_001406791.1:c.1225C>T	NP_001393720.1:p.Arg409Trp	missense
NM_001406792.1:c.1081C>T	NP_001393721.1:p.Arg361Trp	missense
NM_001406793.1:c.1081C>T	NP_001393722.1:p.Arg361Trp	missense
NM_001406794.1:c.1081C>T	NP_001393723.1:p.Arg361Trp	missense
NM_020629.2:c.2530C>T	NP_065680.1:p.Arg844Trp	missense
NM_020630.7:c.2530C>T	NP_065681.1:p.Arg844Trp	missense
NC_000010.11:g.43119668C>T
NC_000010.10:g.43615116C>T
NG_007489.1:g.47600C>T
LRG_518:g.47600C>T
LRG_518t1:c.2530C>T	LRG_518p1:p.Arg844Trp
LRG_518t2:c.2530C>T	LRG_518p2:p.Arg844Trp

... more HGVS ... less HGVS

Protein change

R590W, R361W, R698W, R756W, R514W, R409W, R449W, R505W, R545W, R602W, R712W, R799W, R801W, R500W, R502W, R669W, R748W

Other names

Canonical SPDI

NC_000010.11:43119667: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA008867 dbSNP: rs377767424 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	3595	3717

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 (1)	criteria provided, single submitter	Dec 24, 2023	RCV000456854.17
Multiple endocrine neoplasia type 2A	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 18, 2023	RCV000662786.10
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Nov 16, 2023	RCV001015858.11
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 6, 2019	RCV001588822.11
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	May 9, 2022	RCV002482896.8
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Feb 8, 2024	RCV003460491.2

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 (Sep 29, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785595.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018	Publications: PubMed (1) PubMed: 16818057
Uncertain significance (Sep 06, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001815392.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in a … (more) Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in a patient with Hirschprung disease (Kim 2006); This variant is associated with the following publications: (PMID: 16818057, 21479187) (less)
Uncertain significance (May 09, 2022)	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: SCV002785379.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Apr 18, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018477.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Dec 24, 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: SCV000543825.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 16818057‚ 21479187 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 844 of the RET protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 844 of the RET protein (p.Arg844Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hirschsprung‚Äôs disease (PMID: 16818057). ClinVar contains an entry for this variant (Variation ID: 24950). An algorithm developed specifically for the RET gene suggests that this missense change is likely to be deleterious (PMID: 21479187). 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 (Nov 16, 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: SCV001176738.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 10826520‚ 16818057‚ 21479187 Comment: The p.R844W variant (also known as c.2530C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide … (more) The p.R844W variant (also known as c.2530C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2530. The arginine at codon 844 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208681.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in a patient with Hirschprung disease (Kim 2006); This variant is associated with the following publications: (PMID: 16818057, 21479187)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 844 of the RET protein (p.Arg844Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hirschsprung‚Äôs disease (PMID: 16818057). ClinVar contains an entry for this variant (Variation ID: 24950). An algorithm developed specifically for the RET gene suggests that this missense change is likely to be deleterious (PMID: 21479187). 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.

Comment:

The p.R844W variant (also known as c.2530C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2530. The arginine at codon 844 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene.	Crockett DK	PloS one	2011	PMID: 21479187
Novel mutations of RET gene in Korean patients with sporadic Hirschsprung's disease.	Kim JH	Journal of pediatric surgery	2006	PMID: 16818057
A RET double mutation in the germline of a kindred with FMTC.	Bartsch DK	Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association	2000	PMID: 10826520

Text-mined citations for rs377767424 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.2530C>T (p.Arg844Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377767424 ...