ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2531G>A (p.Arg844Gln)
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(10); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.2531G>A (p.Arg844Gln)
Variation ID: 24951 Accession: VCV000024951.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119669 (GRCh38) [ NCBI UCSC ] 10: 43615117 (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 Apr 4, 2013 Jun 17, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2531G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg844Gln missense NM_000323.2:c.2531G>A NP_000314.1:p.Arg844Gln missense NM_001355216.2:c.1769G>A NP_001342145.1:p.Arg590Gln missense NM_001406743.1:c.2531G>A NP_001393672.1:p.Arg844Gln missense NM_001406744.1:c.2531G>A NP_001393673.1:p.Arg844Gln missense NM_001406759.1:c.2531G>A NP_001393688.1:p.Arg844Gln missense NM_001406760.1:c.2531G>A NP_001393689.1:p.Arg844Gln missense NM_001406761.1:c.2402G>A NP_001393690.1:p.Arg801Gln missense NM_001406762.1:c.2402G>A NP_001393691.1:p.Arg801Gln missense NM_001406763.1:c.2396G>A NP_001393692.1:p.Arg799Gln missense NM_001406764.1:c.2402G>A NP_001393693.1:p.Arg801Gln missense NM_001406765.1:c.2396G>A NP_001393694.1:p.Arg799Gln missense NM_001406766.1:c.2243G>A NP_001393695.1:p.Arg748Gln missense NM_001406767.1:c.2243G>A NP_001393696.1:p.Arg748Gln missense NM_001406768.1:c.2267G>A NP_001393697.1:p.Arg756Gln missense NM_001406769.1:c.2135G>A NP_001393698.1:p.Arg712Gln missense NM_001406770.1:c.2243G>A NP_001393699.1:p.Arg748Gln missense NM_001406771.1:c.2093G>A NP_001393700.1:p.Arg698Gln missense NM_001406772.1:c.2135G>A NP_001393701.1:p.Arg712Gln missense NM_001406773.1:c.2093G>A NP_001393702.1:p.Arg698Gln missense NM_001406774.1:c.2006G>A NP_001393703.1:p.Arg669Gln missense NM_001406775.1:c.1805G>A NP_001393704.1:p.Arg602Gln missense NM_001406776.1:c.1805G>A NP_001393705.1:p.Arg602Gln missense NM_001406777.1:c.1805G>A NP_001393706.1:p.Arg602Gln missense NM_001406778.1:c.1805G>A NP_001393707.1:p.Arg602Gln missense NM_001406779.1:c.1634G>A NP_001393708.1:p.Arg545Gln missense NM_001406780.1:c.1634G>A NP_001393709.1:p.Arg545Gln missense NM_001406781.1:c.1634G>A NP_001393710.1:p.Arg545Gln missense NM_001406782.1:c.1634G>A NP_001393711.1:p.Arg545Gln missense NM_001406783.1:c.1505G>A NP_001393712.1:p.Arg502Gln missense NM_001406784.1:c.1541G>A NP_001393713.1:p.Arg514Gln missense NM_001406785.1:c.1514G>A NP_001393714.1:p.Arg505Gln missense NM_001406786.1:c.1505G>A NP_001393715.1:p.Arg502Gln missense NM_001406787.1:c.1499G>A NP_001393716.1:p.Arg500Gln missense NM_001406788.1:c.1346G>A NP_001393717.1:p.Arg449Gln missense NM_001406789.1:c.1346G>A NP_001393718.1:p.Arg449Gln missense NM_001406790.1:c.1346G>A NP_001393719.1:p.Arg449Gln missense NM_001406791.1:c.1226G>A NP_001393720.1:p.Arg409Gln missense NM_001406792.1:c.1082G>A NP_001393721.1:p.Arg361Gln missense NM_001406793.1:c.1082G>A NP_001393722.1:p.Arg361Gln missense NM_001406794.1:c.1082G>A NP_001393723.1:p.Arg361Gln missense NM_020629.2:c.2531G>A NP_065680.1:p.Arg844Gln missense NM_020630.5:c.2531G>A NM_020630.7:c.2531G>A NP_065681.1:p.Arg844Gln missense NC_000010.11:g.43119669G>A NC_000010.10:g.43615117G>A NG_007489.1:g.47601G>A LRG_518:g.47601G>A LRG_518t1:c.2531G>A LRG_518p1:p.Arg844Gln LRG_518t2:c.2531G>A LRG_518p2:p.Arg844Gln - Protein change
- R590Q, R361Q, R500Q, R698Q, R748Q, R502Q, R756Q, R409Q, R505Q, R514Q, R602Q, R669Q, R712Q, R799Q, R449Q, R545Q, R801Q
- Other names
- p.Arg844Gln
- Canonical SPDI
- NC_000010.11:43119668: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00010
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
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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 |
3526 | 3646 |
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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Jan 18, 2024 | RCV000205855.17 | |
Benign (1) |
criteria provided, single submitter
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Jun 21, 2023 | RCV000575953.12 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000662363.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 22, 2020 | RCV001292765.9 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV001574570.25 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV003466869.1 |
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
(Dec 22, 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:
unknown
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481411.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Apr 03, 2023)
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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:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003928100.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
The RET c.2531G>A (p.Arg844Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, however … (more)
The RET c.2531G>A (p.Arg844Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, however functional studies have demonstrated no damaging effect on RET function (PMID: 29625052). This variant has been reported in individuals with medullary thyroid cancer (PMID: 18058472) and pheochromocytoma (PMID: 35189708). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Apr 18, 2023)
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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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Myriad Genetics, Inc.
Accession: SCV004018474.1
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.
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Uncertain significance
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001801417.4
First in ClinVar: Aug 21, 2021 Last updated: Aug 05, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: RET kinase activity similar to … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: RET kinase activity similar to wildtype (Huang et al., 2018); Observed in individuals with medullary thyroid cancer or breast cancer (Paszko et al., 2007; Guindalini et al., 2022) and co-observed with a pathogenic FH variant in an individual with pheochromocytoma (Ben Aim et al., 2019); This variant is associated with the following publications: (PMID: 20497437, 18058472, 26678667, 27014708, 21479187, 29590403, 25824727, 24699901, 9506724, 19469690, 29386230, 25425582, 34426522, 14633923, 29625052, 30877234, 35264596) (less)
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Uncertain significance
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208661.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jan 18, 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: SCV000260662.9
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 844 of the RET protein (p.Arg844Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 844 of the RET protein (p.Arg844Gln). This variant is present in population databases (rs55947360, gnomAD 0.01%). This missense change has been observed in individual(s) with familial medullary thyroid carcinoma (PMID: 18058472, 24699901, 25425582, 30877234). ClinVar contains an entry for this variant (Variation ID: 24951). 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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 29625052). 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)
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Uncertain significance
(Jan 25, 2017)
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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: SCV000784750.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Apr 06, 2021)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002541061.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Uncertain significance
(Jul 02, 2018)
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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: SCV000838404.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Benign
(Jun 21, 2023)
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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: SCV000674814.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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Uncertain significance
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585215.11
First in ClinVar: Oct 22, 2022 Last updated: Jun 17, 2024 |
Comment:
RET: PM5, PM2:Supporting, PS4:Supporting, BS3:Supporting
Number of individuals with the variant: 2
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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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Expression of LHCGR in Pheochromocytomas Unveils an Endocrine Mechanism Connecting Pregnancy and Epinephrine Overproduction. | Lopez AG | Hypertension (Dallas, Tex. : 1979) | 2022 | PMID: 35189708 |
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. | Toledo RA | Endocrine-related cancer | 2015 | PMID: 25425582 |
RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. | Krampitz GW | Cancer | 2014 | PMID: 24699901 |
Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene. | Crockett DK | PloS one | 2011 | PMID: 21479187 |
RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management. | Mukherjee S | Clinical genetics | 2011 | PMID: 20497437 |
The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. | Paszko Z | Cancer investigation | 2007 | PMID: 18058472 |
A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. | Berndt I | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9506724 |
Text-mined citations for rs55947360 ...
HelpRecord last updated Jun 23, 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.