VCV000405549.11 - ClinVar

NM_020975.6(RET):c.530G>A (p.Arg177Gln)

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.

(5)

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(4); 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.530G>A (p.Arg177Gln)

Variation ID: 405549 Accession: VCV000405549.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43102534 (GRCh38) [ NCBI UCSC ] 10: 43597982 (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	May 26, 2018	May 1, 2024	Nov 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.530G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Arg177Gln	missense
NM_000323.2:c.530G>A	NP_000314.1:p.Arg177Gln	missense
NM_001406743.1:c.530G>A	NP_001393672.1:p.Arg177Gln	missense
NM_001406744.1:c.530G>A	NP_001393673.1:p.Arg177Gln	missense
NM_001406759.1:c.530G>A	NP_001393688.1:p.Arg177Gln	missense
NM_001406760.1:c.530G>A	NP_001393689.1:p.Arg177Gln	missense
NM_001406761.1:c.401G>A	NP_001393690.1:p.Arg134Gln	missense
NM_001406762.1:c.401G>A	NP_001393691.1:p.Arg134Gln	missense
NM_001406763.1:c.530G>A	NP_001393692.1:p.Arg177Gln	missense
NM_001406764.1:c.401G>A	NP_001393693.1:p.Arg134Gln	missense
NM_001406765.1:c.530G>A	NP_001393694.1:p.Arg177Gln	missense
NM_001406768.1:c.401G>A	NP_001393697.1:p.Arg134Gln	missense
NM_001406769.1:c.530G>A	NP_001393698.1:p.Arg177Gln	missense
NM_001406771.1:c.530G>A	NP_001393700.1:p.Arg177Gln	missense
NM_001406772.1:c.530G>A	NP_001393701.1:p.Arg177Gln	missense
NM_001406773.1:c.530G>A	NP_001393702.1:p.Arg177Gln	missense
NM_001406774.1:c.401G>A	NP_001393703.1:p.Arg134Gln	missense
NM_001406779.1:c.530G>A	NP_001393708.1:p.Arg177Gln	missense
NM_001406780.1:c.530G>A	NP_001393709.1:p.Arg177Gln	missense
NM_001406781.1:c.530G>A	NP_001393710.1:p.Arg177Gln	missense
NM_001406782.1:c.530G>A	NP_001393711.1:p.Arg177Gln	missense
NM_001406783.1:c.401G>A	NP_001393712.1:p.Arg134Gln	missense
NM_001406785.1:c.530G>A	NP_001393714.1:p.Arg177Gln	missense
NM_001406786.1:c.401G>A	NP_001393715.1:p.Arg134Gln	missense
NM_001406787.1:c.530G>A	NP_001393716.1:p.Arg177Gln	missense
NM_020629.2:c.530G>A	NP_065680.1:p.Arg177Gln	missense
NM_020630.7:c.530G>A	NP_065681.1:p.Arg177Gln	missense
NC_000010.11:g.43102534G>A
NC_000010.10:g.43597982G>A
NG_007489.1:g.30466G>A
LRG_518:g.30466G>A
LRG_518t1:c.530G>A	LRG_518p1:p.Arg177Gln
LRG_518t2:c.530G>A	LRG_518p2:p.Arg177Gln

... more HGVS ... less HGVS

Protein change

R177Q, R134Q

Other names

Canonical SPDI

NC_000010.11:43102533: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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00006

Links

ClinGen: CA043905 dbSNP: rs759229505 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.
Multiple endocrine neoplasia, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV000473800.11
Familial medullary thyroid carcinoma	Uncertain significance (1)	criteria provided, single submitter	Feb 11, 2019	RCV001294033.2
Hereditary cancer-predisposing syndrome	Likely benign (1)	criteria provided, single submitter	Jan 13, 2022	RCV002348280.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 6, 2023	RCV003322771.1

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 (Feb 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial medullary thyroid carcinoma Affected status: yes Allele origin: paternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001482798.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Oct 04, 2022)	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: SCV000543830.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 177 of the RET protein (p.Arg177Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 177 of the RET protein (p.Arg177Gln). This variant is present in population databases (rs759229505, gnomAD 0.006%). 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: 405549). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 (Apr 06, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004028121.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with melanoma (Huang et al., 2018); This variant … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with melanoma (Huang et al., 2018); This variant is associated with the following publications: (PMID: 14633923, 29625052) (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: SCV004827626.1 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 arginine with glutamine at codon 177 of the RET protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with glutamine at codon 177 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 not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 9/251368 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: 3
Likely benign (Jan 13, 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: SCV002647228.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	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)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 177 of the RET protein (p.Arg177Gln). This variant is present in population databases (rs759229505, gnomAD 0.006%). 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: 405549). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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:

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with melanoma (Huang et al., 2018); This variant is associated with the following publications: (PMID: 14633923, 29625052)

Comment:

This missense variant replaces arginine with glutamine at codon 177 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 not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 9/251368 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 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.

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 rs759229505 ...

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.530G>A (p.Arg177Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs759229505 ...