ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2438G>A (p.Arg813Gln)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.2438G>A (p.Arg813Gln)
Variation ID: 643114 Accession: VCV000643114.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43119576 (GRCh38) [ NCBI UCSC ] 10: 43615024 (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 Aug 14, 2019 Oct 8, 2024 Nov 11, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_020975.6:c.2438G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg813Gln missense NM_000323.2:c.2438G>A NP_000314.1:p.Arg813Gln missense NM_001355216.2:c.1676G>A NP_001342145.1:p.Arg559Gln missense NM_001406743.1:c.2438G>A NP_001393672.1:p.Arg813Gln missense NM_001406744.1:c.2438G>A NP_001393673.1:p.Arg813Gln missense NM_001406759.1:c.2438G>A NP_001393688.1:p.Arg813Gln missense NM_001406760.1:c.2438G>A NP_001393689.1:p.Arg813Gln missense NM_001406761.1:c.2309G>A NP_001393690.1:p.Arg770Gln missense NM_001406762.1:c.2309G>A NP_001393691.1:p.Arg770Gln missense NM_001406763.1:c.2303G>A NP_001393692.1:p.Arg768Gln missense NM_001406764.1:c.2309G>A NP_001393693.1:p.Arg770Gln missense NM_001406765.1:c.2303G>A NP_001393694.1:p.Arg768Gln missense NM_001406766.1:c.2150G>A NP_001393695.1:p.Arg717Gln missense NM_001406767.1:c.2150G>A NP_001393696.1:p.Arg717Gln missense NM_001406768.1:c.2174G>A NP_001393697.1:p.Arg725Gln missense NM_001406769.1:c.2042G>A NP_001393698.1:p.Arg681Gln missense NM_001406770.1:c.2150G>A NP_001393699.1:p.Arg717Gln missense NM_001406771.1:c.2000G>A NP_001393700.1:p.Arg667Gln missense NM_001406772.1:c.2042G>A NP_001393701.1:p.Arg681Gln missense NM_001406773.1:c.2000G>A NP_001393702.1:p.Arg667Gln missense NM_001406774.1:c.1913G>A NP_001393703.1:p.Arg638Gln missense NM_001406775.1:c.1712G>A NP_001393704.1:p.Arg571Gln missense NM_001406776.1:c.1712G>A NP_001393705.1:p.Arg571Gln missense NM_001406777.1:c.1712G>A NP_001393706.1:p.Arg571Gln missense NM_001406778.1:c.1712G>A NP_001393707.1:p.Arg571Gln missense NM_001406779.1:c.1541G>A NP_001393708.1:p.Arg514Gln missense NM_001406780.1:c.1541G>A NP_001393709.1:p.Arg514Gln missense NM_001406781.1:c.1541G>A NP_001393710.1:p.Arg514Gln missense NM_001406782.1:c.1541G>A NP_001393711.1:p.Arg514Gln missense NM_001406783.1:c.1412G>A NP_001393712.1:p.Arg471Gln missense NM_001406784.1:c.1448G>A NP_001393713.1:p.Arg483Gln missense NM_001406785.1:c.1421G>A NP_001393714.1:p.Arg474Gln missense NM_001406786.1:c.1412G>A NP_001393715.1:p.Arg471Gln missense NM_001406787.1:c.1406G>A NP_001393716.1:p.Arg469Gln missense NM_001406788.1:c.1253G>A NP_001393717.1:p.Arg418Gln missense NM_001406789.1:c.1253G>A NP_001393718.1:p.Arg418Gln missense NM_001406790.1:c.1253G>A NP_001393719.1:p.Arg418Gln missense NM_001406791.1:c.1133G>A NP_001393720.1:p.Arg378Gln missense NM_001406792.1:c.989G>A NP_001393721.1:p.Arg330Gln missense NM_001406793.1:c.989G>A NP_001393722.1:p.Arg330Gln missense NM_001406794.1:c.989G>A NP_001393723.1:p.Arg330Gln missense NM_020629.2:c.2438G>A NP_065680.1:p.Arg813Gln missense NM_020630.7:c.2438G>A NP_065681.1:p.Arg813Gln missense NC_000010.11:g.43119576G>A NC_000010.10:g.43615024G>A NG_007489.1:g.47508G>A LRG_518:g.47508G>A LRG_518t1:c.2438G>A LRG_518p1:p.Arg813Gln LRG_518t2:c.2438G>A LRG_518p2:p.Arg813Gln - Protein change
- R813Q, R559Q, R330Q, R378Q, R474Q, R717Q, R770Q, R471Q, R571Q, R418Q, R469Q, R514Q, R667Q, R681Q, R725Q, R768Q, R483Q, R638Q
- Other names
- -
- Canonical SPDI
- NC_000010.11:43119575:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
---|---|---|---|---|---|---|
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 |
3592 | 3714 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 11, 2023 | RCV000796744.14 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jul 6, 2021 | RCV002458436.2 | |
RET-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Dec 17, 2023 | RCV004538092.2 |
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
(Nov 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000936269.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 813 of the RET protein (p.Arg813Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 813 of the RET protein (p.Arg813Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 10090908, 22729463). ClinVar contains an entry for this variant (Variation ID: 643114). 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 disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 22729463, 22837065). 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
(Aug 28, 2023)
|
criteria provided, single submitter
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: SCV004827965.1
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 813 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 813 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro functional studies have shown this variant reduces RET phosphorylation and colony formation (PMID: 22729463, 22837065). This variant has been reported in an individual affected with Hirschsprung disease (PMID: 10090908). This variant has been identified in 1/242298 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: 1
|
|
Uncertain significance
(Jul 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002737560.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R813Q variant (also known as c.2438G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide … (more)
The p.R813Q variant (also known as c.2438G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide position 2438. The arginine at codon 813 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with Hirschsprung disease (Auricchio A et al. Am J Hum Genet. 1999 Apr;64:1216-21; Hyndman BD et al. Hum Mutat. 2013 Jan;34:132-42). In in vitro functional assays, this alteration demonstrated impaired RET phosphorylation and colony formation (Hyndman BD et al. Hum Mutat. 2013 Jan;34:132-42; Chatterjee R et al. Hum Genet. 2012 Nov;131:1725-38). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. 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
(Dec 17, 2023)
|
no assertion criteria provided
Method: clinical testing
|
RET-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004709318.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The RET c.2438G>A variant is predicted to result in the amino acid substitution p.Arg813Gln. This variant was reported in individuals with Hirschsprung disease and CAKUT/duplicating … (more)
The RET c.2438G>A variant is predicted to result in the amino acid substitution p.Arg813Gln. This variant was reported in individuals with Hirschsprung disease and CAKUT/duplicating collecting system phenotypes (Table 1, Auricchio et al. 1999. PubMed ID: 10090908; Table 2 Chatterjee et al. 2012. PubMed ID: 22729463). In vitro functional studies support this variant impacts the phosphorylation activity of the RET protein (Hyndman et al. 2012. PubMed ID: 22837065). Different missense variants impacting the same amino acid residue (p.Arg813Trp, p.Arg813Leu) have been reported in individuals with Hirschsprung disease phenotypes (Virtanen et al. 2019. PubMed ID: 30031151; Table S1, Jannot et al. 2012. PubMed ID: 22395866). This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
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 |
---|---|---|---|---|
Multiple functional effects of RET kinase domain sequence variants in Hirschsprung disease. | Hyndman BD | Human mutation | 2013 | PMID: 22837065 |
Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. | Chatterjee R | Human genetics | 2012 | PMID: 22729463 |
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 |
Text-mined citations for rs1318733775 ...
HelpRecord last updated Oct 08, 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.