ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.539G>A (p.Arg180Gln)
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.
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(6); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.539G>A (p.Arg180Gln)
Variation ID: 161360 Accession: VCV000161360.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43102543 (GRCh38) [ NCBI UCSC ] 10: 43597991 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 7, 2014 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.539G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg180Gln missense NM_000323.2:c.539G>A NP_000314.1:p.Arg180Gln missense NM_001406743.1:c.539G>A NP_001393672.1:p.Arg180Gln missense NM_001406744.1:c.539G>A NP_001393673.1:p.Arg180Gln missense NM_001406759.1:c.539G>A NP_001393688.1:p.Arg180Gln missense NM_001406760.1:c.539G>A NP_001393689.1:p.Arg180Gln missense NM_001406761.1:c.410G>A NP_001393690.1:p.Arg137Gln missense NM_001406762.1:c.410G>A NP_001393691.1:p.Arg137Gln missense NM_001406763.1:c.539G>A NP_001393692.1:p.Arg180Gln missense NM_001406764.1:c.410G>A NP_001393693.1:p.Arg137Gln missense NM_001406765.1:c.539G>A NP_001393694.1:p.Arg180Gln missense NM_001406768.1:c.410G>A NP_001393697.1:p.Arg137Gln missense NM_001406769.1:c.539G>A NP_001393698.1:p.Arg180Gln missense NM_001406771.1:c.539G>A NP_001393700.1:p.Arg180Gln missense NM_001406772.1:c.539G>A NP_001393701.1:p.Arg180Gln missense NM_001406773.1:c.539G>A NP_001393702.1:p.Arg180Gln missense NM_001406774.1:c.410G>A NP_001393703.1:p.Arg137Gln missense NM_001406779.1:c.539G>A NP_001393708.1:p.Arg180Gln missense NM_001406780.1:c.539G>A NP_001393709.1:p.Arg180Gln missense NM_001406781.1:c.539G>A NP_001393710.1:p.Arg180Gln missense NM_001406782.1:c.539G>A NP_001393711.1:p.Arg180Gln missense NM_001406783.1:c.410G>A NP_001393712.1:p.Arg137Gln missense NM_001406785.1:c.539G>A NP_001393714.1:p.Arg180Gln missense NM_001406786.1:c.410G>A NP_001393715.1:p.Arg137Gln missense NM_001406787.1:c.539G>A NP_001393716.1:p.Arg180Gln missense NM_020629.2:c.539G>A NP_065680.1:p.Arg180Gln missense NM_020630.7:c.539G>A NP_065681.1:p.Arg180Gln missense NC_000010.11:g.43102543G>A NC_000010.10:g.43597991G>A NG_007489.1:g.30475G>A LRG_518:g.30475G>A LRG_518t1:c.539G>A LRG_518p1:p.Arg180Gln LRG_518t2:c.539G>A LRG_518p2:p.Arg180Gln - Protein change
- R180Q, R137Q
- Other names
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- Canonical SPDI
- NC_000010.11:43102542:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00014
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 | ||
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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. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3522 | 3642 |
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jun 1, 2014 | RCV000148786.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 5, 2024 | RCV000197537.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000410075.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2015 | RCV000412078.3 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 22, 2020 | RCV001024031.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 10, 2020 | RCV001294034.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 11, 2023 | RCV003736605.1 |
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. |
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Uncertain significance
(Apr 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial medullary thyroid carcinoma
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482799.1 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].
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Uncertain significance
(Jun 01, 2014)
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criteria provided, single submitter
Method: research
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Hirschsprung disease
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190524.2 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138020.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Dec 18, 2015)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489769.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Dec 18, 2015)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489770.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Sep 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562535.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The RET c.539G>A; p.Arg180Gln variant (rs370736139) is reported in the literature in an individual affected with Hirschsprung disease (Hofstra 2000). This variant is also reported … (more)
The RET c.539G>A; p.Arg180Gln variant (rs370736139) is reported in the literature in an individual affected with Hirschsprung disease (Hofstra 2000). This variant is also reported in ClinVar (Variation ID: 161360). This variant is found in the Latino population with an allele frequency of 0.08% (27/35,432 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.223). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hofstra RM et al. RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat. 2000;15(5):418-29. PMID: 10790203. (less)
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Likely benign
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000253568.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004838627.1
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)
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Comment:
This missense variant replaces arginine with glutamine at codon 180 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 180 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 MEN2 or medullary thyroid carcinoma. This variant has been reported in an individual affected with Hirschsprung disease (PMID: 10790203). This variant has been identified in 37/282728 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: 11
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Likely benign
(Oct 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001185984.4
First in ClinVar: Mar 16, 2020 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)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. | So MT | PloS one | 2011 | PMID: 22174939 |
RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. | Hofstra RM | Human mutation | 2000 | PMID: 10790203 |
Text-mined citations for rs370736139 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.