VCV000224354.15 - ClinVar

NM_020975.6(RET):c.1201A>T (p.Ser401Cys)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.1201A>T (p.Ser401Cys)

Variation ID: 224354 Accession: VCV000224354.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43109168 (GRCh38) [ NCBI UCSC ] 10: 43604616 (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	Feb 8, 2017	Oct 8, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.1201A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Ser401Cys	missense
NM_000323.2:c.1201A>T	NP_000314.1:p.Ser401Cys	missense
NM_001355216.2:c.439A>T	NP_001342145.1:p.Ser147Cys	missense
NM_001406743.1:c.1201A>T	NP_001393672.1:p.Ser401Cys	missense
NM_001406744.1:c.1201A>T	NP_001393673.1:p.Ser401Cys	missense
NM_001406759.1:c.1201A>T	NP_001393688.1:p.Ser401Cys	missense
NM_001406760.1:c.1201A>T	NP_001393689.1:p.Ser401Cys	missense
NM_001406761.1:c.1072A>T	NP_001393690.1:p.Ser358Cys	missense
NM_001406762.1:c.1072A>T	NP_001393691.1:p.Ser358Cys	missense
NM_001406763.1:c.1201A>T	NP_001393692.1:p.Ser401Cys	missense
NM_001406764.1:c.1072A>T	NP_001393693.1:p.Ser358Cys	missense
NM_001406765.1:c.1201A>T	NP_001393694.1:p.Ser401Cys	missense
NM_001406766.1:c.913A>T	NP_001393695.1:p.Ser305Cys	missense
NM_001406767.1:c.913A>T	NP_001393696.1:p.Ser305Cys	missense
NM_001406768.1:c.1072A>T	NP_001393697.1:p.Ser358Cys	missense
NM_001406770.1:c.913A>T	NP_001393699.1:p.Ser305Cys	missense
NM_001406771.1:c.763A>T	NP_001393700.1:p.Ser255Cys	missense
NM_001406773.1:c.763A>T	NP_001393702.1:p.Ser255Cys	missense
NM_001406775.1:c.475A>T	NP_001393704.1:p.Ser159Cys	missense
NM_001406776.1:c.475A>T	NP_001393705.1:p.Ser159Cys	missense
NM_001406777.1:c.475A>T	NP_001393706.1:p.Ser159Cys	missense
NM_001406778.1:c.475A>T	NP_001393707.1:p.Ser159Cys	missense
NM_001406784.1:c.211A>T	NP_001393713.1:p.Ser71Cys	missense
NM_020629.2:c.1201A>T	NP_065680.1:p.Ser401Cys	missense
NM_020630.7:c.1201A>T	NP_065681.1:p.Ser401Cys	missense
NC_000010.11:g.43109168A>T
NC_000010.10:g.43604616A>T
NG_007489.1:g.37100A>T
LRG_518:g.37100A>T
LRG_518t1:c.1201A>T	LRG_518p1:p.Ser401Cys
LRG_518t2:c.1201A>T	LRG_518p2:p.Ser401Cys

... more HGVS ... less HGVS

Protein change

S401C, S147C, S255C, S358C, S71C, S159C, S305C

Other names

Canonical SPDI

NC_000010.11:43109167:A: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.

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA032120 dbSNP: rs140638866 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.
Congenital anomaly of kidney and urinary tract	Uncertain significance (1)	criteria provided, single submitter	-	RCV000416603.2
Multiple endocrine neoplasia, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000560396.13
Hereditary cancer-predisposing syndrome	Likely benign (1)	criteria provided, single submitter	May 19, 2023	RCV001010283.5
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Sep 7, 2023	RCV003468970.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 20, 2023	RCV004721300.1

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 (-)	criteria provided, single submitter (Bekheirnia et al. (Genet Med. 2016)) Method: research	Congenital anomaly of kidney and urinary tract (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000265661.1 First in ClinVar: Feb 08, 2017 Last updated: Feb 08, 2017	Publications: PubMed (1) PubMed: 27657687 Clinical Features: Anterior urethral valves (present) , Bilateral multicystic dysplastic kidney (present) Family history: yes
Uncertain significance (Jan 04, 2024)	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: SCV000658396.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 27657687 Comment: This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 401 of the RET protein … (more) This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 401 of the RET protein (p.Ser401Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital anomalies of the kidney and urinary tract (PMID: 27657687). ClinVar contains an entry for this variant (Variation ID: 224354). 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)
Likely benign (May 19, 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: SCV001170456.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 27657687‚ 29641532 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Sep 07, 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: SCV004208688.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain Significance (Jan 03, 2024)	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: SCV004822634.1 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)	Publications: PubMed (1) PubMed: 27657687 Comment: This missense variant replaces serine with cysteine at codon 401 of the RET protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces serine with cysteine at codon 401 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 been reported in an individual affected with congenital anomalies of the kidney and urinary tract (PMID: 27657687). This variant has been identified in 11/282496 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: 15
Uncertain significance (Jul 20, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005327441.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in any cases, but was observed in unaffected … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in any cases, but was observed in unaffected controls from a melanoma study (Pritchard et al., 2018); Observed in an individual with anterior urethral valves, hearing loss, speech articulation problem, and neurocognitive dysfunction (Bekheirnia et al., 2017); This variant is associated with the following publications: (PMID: 14633923, 29641532, 27657687) (less)

Comment:

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 401 of the RET protein (p.Ser401Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital anomalies of the kidney and urinary tract (PMID: 27657687). ClinVar contains an entry for this variant (Variation ID: 224354). 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.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This missense variant replaces serine with cysteine at codon 401 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 been reported in an individual affected with congenital anomalies of the kidney and urinary tract (PMID: 27657687). This variant has been identified in 11/282496 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:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in any cases, but was observed in unaffected controls from a melanoma study (Pritchard et al., 2018); Observed in an individual with anterior urethral valves, hearing loss, speech articulation problem, and neurocognitive dysfunction (Bekheirnia et al., 2017); This variant is associated with the following publications: (PMID: 14633923, 29641532, 27657687)

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
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.	Pritchard AL	PloS one	2018	PMID: 29641532
Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.	Bekheirnia MR	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27657687

Text-mined citations for rs140638866 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.1201A>T (p.Ser401Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140638866 ...