ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1893C>G (p.Asp631Glu)
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
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NM_020975.6(RET):c.1893C>G (p.Asp631Glu)
Variation ID: 2123053 Accession: VCV002123053.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43114493 (GRCh38) [ NCBI UCSC ] 10: 43609941 (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 Feb 8, 2023 Feb 20, 2024 May 9, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1893C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Asp631Glu missense NM_000323.2:c.1893C>G NP_000314.1:p.Asp631Glu missense NM_001355216.2:c.1131C>G NP_001342145.1:p.Asp377Glu missense NM_001406743.1:c.1893C>G NP_001393672.1:p.Asp631Glu missense NM_001406744.1:c.1893C>G NP_001393673.1:p.Asp631Glu missense NM_001406759.1:c.1893C>G NP_001393688.1:p.Asp631Glu missense NM_001406760.1:c.1893C>G NP_001393689.1:p.Asp631Glu missense NM_001406761.1:c.1764C>G NP_001393690.1:p.Asp588Glu missense NM_001406762.1:c.1764C>G NP_001393691.1:p.Asp588Glu missense NM_001406764.1:c.1764C>G NP_001393693.1:p.Asp588Glu missense NM_001406766.1:c.1605C>G NP_001393695.1:p.Asp535Glu missense NM_001406767.1:c.1605C>G NP_001393696.1:p.Asp535Glu missense NM_001406769.1:c.1497C>G NP_001393698.1:p.Asp499Glu missense NM_001406770.1:c.1605C>G NP_001393699.1:p.Asp535Glu missense NM_001406771.1:c.1455C>G NP_001393700.1:p.Asp485Glu missense NM_001406772.1:c.1497C>G NP_001393701.1:p.Asp499Glu missense NM_001406773.1:c.1455C>G NP_001393702.1:p.Asp485Glu missense NM_001406774.1:c.1368C>G NP_001393703.1:p.Asp456Glu missense NM_001406775.1:c.1167C>G NP_001393704.1:p.Asp389Glu missense NM_001406776.1:c.1167C>G NP_001393705.1:p.Asp389Glu missense NM_001406777.1:c.1167C>G NP_001393706.1:p.Asp389Glu missense NM_001406778.1:c.1167C>G NP_001393707.1:p.Asp389Glu missense NM_001406779.1:c.996C>G NP_001393708.1:p.Asp332Glu missense NM_001406780.1:c.996C>G NP_001393709.1:p.Asp332Glu missense NM_001406781.1:c.996C>G NP_001393710.1:p.Asp332Glu missense NM_001406782.1:c.996C>G NP_001393711.1:p.Asp332Glu missense NM_001406783.1:c.867C>G NP_001393712.1:p.Asp289Glu missense NM_001406784.1:c.903C>G NP_001393713.1:p.Asp301Glu missense NM_001406785.1:c.876C>G NP_001393714.1:p.Asp292Glu missense NM_001406786.1:c.867C>G NP_001393715.1:p.Asp289Glu missense NM_001406788.1:c.708C>G NP_001393717.1:p.Asp236Glu missense NM_001406789.1:c.708C>G NP_001393718.1:p.Asp236Glu missense NM_001406790.1:c.708C>G NP_001393719.1:p.Asp236Glu missense NM_001406791.1:c.588C>G NP_001393720.1:p.Asp196Glu missense NM_001406792.1:c.444C>G NP_001393721.1:p.Asp148Glu missense NM_001406793.1:c.444C>G NP_001393722.1:p.Asp148Glu missense NM_001406794.1:c.444C>G NP_001393723.1:p.Asp148Glu missense NM_020629.2:c.1893C>G NP_065680.1:p.Asp631Glu missense NM_020630.7:c.1893C>G NP_065681.1:p.Asp631Glu missense NC_000010.11:g.43114493C>G NC_000010.10:g.43609941C>G NG_007489.1:g.42425C>G LRG_518:g.42425C>G LRG_518t1:c.1893C>G LRG_518p1:p.Asp631Glu LRG_518t2:c.1893C>G LRG_518p2:p.Asp631Glu - Protein change
- D289E, D377E, D535E, D148E, D292E, D456E, D631E, D236E, D301E, D485E, D499E, D196E, D332E, D389E, D588E
- Other names
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- Canonical SPDI
- NC_000010.11:43114492:C:G
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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
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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May 9, 2022 | RCV003047173.2 |
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
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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
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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
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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
(May 09, 2022)
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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: SCV003341829.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 631 of the RET … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 631 of the RET protein (p.Asp631Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 15858153). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Asp631 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16839264). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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A rare extracellular D631Y germline mutation of the RET proto-oncogene in two Korean families with multiple endocrine neoplasia 2A. | Bae SJ | Thyroid : official journal of the American Thyroid Association | 2006 | PMID: 16839264 |
Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. | Ahmed SA | The Journal of molecular diagnostics : JMD | 2005 | PMID: 15858153 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 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.