ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2290G>A (p.Ala764Thr)
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(3); 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.2290G>A (p.Ala764Thr)
Variation ID: 486317 Accession: VCV000486317.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43118378 (GRCh38) [ NCBI UCSC ] 10: 43613826 (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 Jan 1, 2018 Apr 20, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2290G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Ala764Thr missense NM_000323.2:c.2290G>A NP_000314.1:p.Ala764Thr missense NM_001355216.2:c.1528G>A NP_001342145.1:p.Ala510Thr missense NM_001406743.1:c.2290G>A NP_001393672.1:p.Ala764Thr missense NM_001406744.1:c.2290G>A NP_001393673.1:p.Ala764Thr missense NM_001406759.1:c.2290G>A NP_001393688.1:p.Ala764Thr missense NM_001406760.1:c.2290G>A NP_001393689.1:p.Ala764Thr missense NM_001406761.1:c.2161G>A NP_001393690.1:p.Ala721Thr missense NM_001406762.1:c.2161G>A NP_001393691.1:p.Ala721Thr missense NM_001406763.1:c.2155G>A NP_001393692.1:p.Ala719Thr missense NM_001406764.1:c.2161G>A NP_001393693.1:p.Ala721Thr missense NM_001406765.1:c.2155G>A NP_001393694.1:p.Ala719Thr missense NM_001406766.1:c.2002G>A NP_001393695.1:p.Ala668Thr missense NM_001406767.1:c.2002G>A NP_001393696.1:p.Ala668Thr missense NM_001406768.1:c.2026G>A NP_001393697.1:p.Ala676Thr missense NM_001406769.1:c.1894G>A NP_001393698.1:p.Ala632Thr missense NM_001406770.1:c.2002G>A NP_001393699.1:p.Ala668Thr missense NM_001406771.1:c.1852G>A NP_001393700.1:p.Ala618Thr missense NM_001406772.1:c.1894G>A NP_001393701.1:p.Ala632Thr missense NM_001406773.1:c.1852G>A NP_001393702.1:p.Ala618Thr missense NM_001406774.1:c.1765G>A NP_001393703.1:p.Ala589Thr missense NM_001406775.1:c.1564G>A NP_001393704.1:p.Ala522Thr missense NM_001406776.1:c.1564G>A NP_001393705.1:p.Ala522Thr missense NM_001406777.1:c.1564G>A NP_001393706.1:p.Ala522Thr missense NM_001406778.1:c.1564G>A NP_001393707.1:p.Ala522Thr missense NM_001406779.1:c.1393G>A NP_001393708.1:p.Ala465Thr missense NM_001406780.1:c.1393G>A NP_001393709.1:p.Ala465Thr missense NM_001406781.1:c.1393G>A NP_001393710.1:p.Ala465Thr missense NM_001406782.1:c.1393G>A NP_001393711.1:p.Ala465Thr missense NM_001406783.1:c.1264G>A NP_001393712.1:p.Ala422Thr missense NM_001406784.1:c.1300G>A NP_001393713.1:p.Ala434Thr missense NM_001406785.1:c.1273G>A NP_001393714.1:p.Ala425Thr missense NM_001406786.1:c.1264G>A NP_001393715.1:p.Ala422Thr missense NM_001406787.1:c.1258G>A NP_001393716.1:p.Ala420Thr missense NM_001406788.1:c.1105G>A NP_001393717.1:p.Ala369Thr missense NM_001406789.1:c.1105G>A NP_001393718.1:p.Ala369Thr missense NM_001406790.1:c.1105G>A NP_001393719.1:p.Ala369Thr missense NM_001406791.1:c.985G>A NP_001393720.1:p.Ala329Thr missense NM_001406792.1:c.841G>A NP_001393721.1:p.Ala281Thr missense NM_001406793.1:c.841G>A NP_001393722.1:p.Ala281Thr missense NM_001406794.1:c.841G>A NP_001393723.1:p.Ala281Thr missense NM_020629.2:c.2290G>A NP_065680.1:p.Ala764Thr missense NM_020630.7:c.2290G>A NP_065681.1:p.Ala764Thr missense NC_000010.11:g.43118378G>A NC_000010.10:g.43613826G>A NG_007489.1:g.46310G>A LRG_518:g.46310G>A LRG_518t1:c.2290G>A LRG_518p1:p.Ala764Thr LRG_518t2:c.2290G>A LRG_518p2:p.Ala764Thr - Protein change
- A764T, A510T, A369T, A422T, A425T, A589T, A618T, A668T, A721T, A329T, A434T, A465T, A420T, A522T, A632T, A676T, A281T, A719T
- Other names
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- Canonical SPDI
- NC_000010.11:43118377: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.
Exome Aggregation Consortium (ExAC) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
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 |
3446 | 3566 |
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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Benign (1) |
criteria provided, single submitter
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Jan 26, 2023 | RCV000576114.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000654575.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2022 | RCV002476250.1 |
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
(Jan 12, 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: SCV002783657.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jan 26, 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: SCV000674840.5
First in ClinVar: Jan 01, 2018 Last updated: Apr 15, 2023 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as 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)
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Uncertain significance
(Jan 26, 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: SCV000776469.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 764 of the RET protein (p.Ala764Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 764 of the RET protein (p.Ala764Thr). This variant is present in population databases (rs748799148, gnomAD 0.007%). 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: 486317). 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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Uncertain Significance
(Dec 01, 2023)
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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: SCV004828179.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces alanine with threonine at codon 764 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces alanine with threonine at codon 764 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 9/251010 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: 7
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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
HelpThere 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 rs748799148 ...
HelpRecord last updated Apr 20, 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.