ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2657G>A (p.Arg886Gln)
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(8); Likely 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.2657G>A (p.Arg886Gln)
Variation ID: 543745 Accession: VCV000543745.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43120130 (GRCh38) [ NCBI UCSC ] 10: 43615578 (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 Oct 10, 2018 Feb 20, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2657G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg886Gln missense NM_000323.2:c.2657G>A NP_000314.1:p.Arg886Gln missense NM_001355216.2:c.1895G>A NP_001342145.1:p.Arg632Gln missense NM_001406743.1:c.2657G>A NP_001393672.1:p.Arg886Gln missense NM_001406744.1:c.2657G>A NP_001393673.1:p.Arg886Gln missense NM_001406759.1:c.2657G>A NP_001393688.1:p.Arg886Gln missense NM_001406760.1:c.2657G>A NP_001393689.1:p.Arg886Gln missense NM_001406761.1:c.2528G>A NP_001393690.1:p.Arg843Gln missense NM_001406762.1:c.2528G>A NP_001393691.1:p.Arg843Gln missense NM_001406763.1:c.2522G>A NP_001393692.1:p.Arg841Gln missense NM_001406764.1:c.2528G>A NP_001393693.1:p.Arg843Gln missense NM_001406765.1:c.2522G>A NP_001393694.1:p.Arg841Gln missense NM_001406766.1:c.2369G>A NP_001393695.1:p.Arg790Gln missense NM_001406767.1:c.2369G>A NP_001393696.1:p.Arg790Gln missense NM_001406768.1:c.2393G>A NP_001393697.1:p.Arg798Gln missense NM_001406769.1:c.2261G>A NP_001393698.1:p.Arg754Gln missense NM_001406770.1:c.2369G>A NP_001393699.1:p.Arg790Gln missense NM_001406771.1:c.2219G>A NP_001393700.1:p.Arg740Gln missense NM_001406772.1:c.2261G>A NP_001393701.1:p.Arg754Gln missense NM_001406773.1:c.2219G>A NP_001393702.1:p.Arg740Gln missense NM_001406774.1:c.2132G>A NP_001393703.1:p.Arg711Gln missense NM_001406775.1:c.1931G>A NP_001393704.1:p.Arg644Gln missense NM_001406776.1:c.1931G>A NP_001393705.1:p.Arg644Gln missense NM_001406777.1:c.1931G>A NP_001393706.1:p.Arg644Gln missense NM_001406778.1:c.1931G>A NP_001393707.1:p.Arg644Gln missense NM_001406779.1:c.1760G>A NP_001393708.1:p.Arg587Gln missense NM_001406780.1:c.1760G>A NP_001393709.1:p.Arg587Gln missense NM_001406781.1:c.1760G>A NP_001393710.1:p.Arg587Gln missense NM_001406782.1:c.1760G>A NP_001393711.1:p.Arg587Gln missense NM_001406783.1:c.1631G>A NP_001393712.1:p.Arg544Gln missense NM_001406784.1:c.1667G>A NP_001393713.1:p.Arg556Gln missense NM_001406785.1:c.1640G>A NP_001393714.1:p.Arg547Gln missense NM_001406786.1:c.1631G>A NP_001393715.1:p.Arg544Gln missense NM_001406787.1:c.1625G>A NP_001393716.1:p.Arg542Gln missense NM_001406788.1:c.1472G>A NP_001393717.1:p.Arg491Gln missense NM_001406789.1:c.1472G>A NP_001393718.1:p.Arg491Gln missense NM_001406790.1:c.1472G>A NP_001393719.1:p.Arg491Gln missense NM_001406791.1:c.1352G>A NP_001393720.1:p.Arg451Gln missense NM_001406792.1:c.1208G>A NP_001393721.1:p.Arg403Gln missense NM_001406793.1:c.1208G>A NP_001393722.1:p.Arg403Gln missense NM_001406794.1:c.1208G>A NP_001393723.1:p.Arg403Gln missense NM_020629.2:c.2657G>A NP_065680.1:p.Arg886Gln missense NM_020630.7:c.2657G>A NP_065681.1:p.Arg886Gln missense NC_000010.11:g.43120130G>A NC_000010.10:g.43615578G>A NG_007489.1:g.48062G>A LRG_518:g.48062G>A LRG_518t1:c.2657G>A LRG_518p1:p.Arg886Gln LRG_518t2:c.2657G>A LRG_518p2:p.Arg886Gln - Protein change
- R886Q, R632Q, R451Q, R491Q, R556Q, R644Q, R740Q, R790Q, R542Q, R547Q, R843Q, R403Q, R754Q, R841Q, R544Q, R587Q, R711Q, R798Q
- Other names
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- Canonical SPDI
- NC_000010.11:43120129: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), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00011
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 |
3382 | 3500 |
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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Dec 15, 2023 | RCV000654581.16 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 18, 2022 | RCV000708758.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 29, 2022 | RCV002284418.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 24, 2022 | RCV002477456.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 12, 2018 | RCV003313129.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV003459554.1 |
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
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822197.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Nov 20, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529988.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Feb 18, 2022)
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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: SCV001177161.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Familial medullary thyroid carcinoma MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB Pheochromocytoma MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002800704.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 29, 2022)
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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: SCV002574288.2
First in ClinVar: Sep 24, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with medullary thyroid carcinoma, Hirschsprung's disease, and breast cancer … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with medullary thyroid carcinoma, Hirschsprung's disease, and breast cancer (Carter et al., 2012; Amosenko et al., 2018; Chen et al., 2020); This variant is associated with the following publications: (PMID: 31159747, 28946813, 14633923, 32091409, Amosenko2018[casereport], 22648184) (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011449.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Jul 12, 2018)
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criteria provided, single submitter
Method: research
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Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
Affected status: yes
Allele origin:
paternal
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Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital
Accession: SCV004012938.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
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Uncertain significance
(Aug 28, 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: SCV004208698.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Dec 15, 2023)
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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: SCV000776475.8
First in ClinVar: May 28, 2018 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 886 of the RET protein (p.Arg886Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 886 of the RET protein (p.Arg886Gln). This variant is present in population databases (rs373594744, gnomAD 0.03%). This missense change has been observed in individual(s) with Hirschsprung disease, medullary thyroid cancer, and/or pheochromocytoma (PMID: 22648184, 28946813, 33981013). ClinVar contains an entry for this variant (Variation ID: 543745). 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. 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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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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Stepwise ABC system for classification of any type of genetic variant. | Houge G | European journal of human genetics : EJHG | 2022 | PMID: 33981013 |
Comparison of BRCA versus non-BRCA germline mutations and associated somatic mutation profiles in patients with unselected breast cancer. | Chen B | Aging | 2020 | PMID: 32091409 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers. | Lebeault M | Thyroid : official journal of the American Thyroid Association | 2017 | PMID: 28946813 |
Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. | Carter TC | Journal of human genetics | 2012 | PMID: 22648184 |
Text-mined citations for rs373594744 ...
HelpRecord last updated Apr 15, 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.