ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2411T>C (p.Val804Ala)
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.2411T>C (p.Val804Ala)
Variation ID: 1962568 Accession: VCV001962568.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119549 (GRCh38) [ NCBI UCSC ] 10: 43614997 (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 7, 2023 May 1, 2024 Feb 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2411T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Val804Ala missense NM_000323.2:c.2411T>C NP_000314.1:p.Val804Ala missense NM_001355216.2:c.1649T>C NP_001342145.1:p.Val550Ala missense NM_001406743.1:c.2411T>C NP_001393672.1:p.Val804Ala missense NM_001406744.1:c.2411T>C NP_001393673.1:p.Val804Ala missense NM_001406759.1:c.2411T>C NP_001393688.1:p.Val804Ala missense NM_001406760.1:c.2411T>C NP_001393689.1:p.Val804Ala missense NM_001406761.1:c.2282T>C NP_001393690.1:p.Val761Ala missense NM_001406762.1:c.2282T>C NP_001393691.1:p.Val761Ala missense NM_001406763.1:c.2276T>C NP_001393692.1:p.Val759Ala missense NM_001406764.1:c.2282T>C NP_001393693.1:p.Val761Ala missense NM_001406765.1:c.2276T>C NP_001393694.1:p.Val759Ala missense NM_001406766.1:c.2123T>C NP_001393695.1:p.Val708Ala missense NM_001406767.1:c.2123T>C NP_001393696.1:p.Val708Ala missense NM_001406768.1:c.2147T>C NP_001393697.1:p.Val716Ala missense NM_001406769.1:c.2015T>C NP_001393698.1:p.Val672Ala missense NM_001406770.1:c.2123T>C NP_001393699.1:p.Val708Ala missense NM_001406771.1:c.1973T>C NP_001393700.1:p.Val658Ala missense NM_001406772.1:c.2015T>C NP_001393701.1:p.Val672Ala missense NM_001406773.1:c.1973T>C NP_001393702.1:p.Val658Ala missense NM_001406774.1:c.1886T>C NP_001393703.1:p.Val629Ala missense NM_001406775.1:c.1685T>C NP_001393704.1:p.Val562Ala missense NM_001406776.1:c.1685T>C NP_001393705.1:p.Val562Ala missense NM_001406777.1:c.1685T>C NP_001393706.1:p.Val562Ala missense NM_001406778.1:c.1685T>C NP_001393707.1:p.Val562Ala missense NM_001406779.1:c.1514T>C NP_001393708.1:p.Val505Ala missense NM_001406780.1:c.1514T>C NP_001393709.1:p.Val505Ala missense NM_001406781.1:c.1514T>C NP_001393710.1:p.Val505Ala missense NM_001406782.1:c.1514T>C NP_001393711.1:p.Val505Ala missense NM_001406783.1:c.1385T>C NP_001393712.1:p.Val462Ala missense NM_001406784.1:c.1421T>C NP_001393713.1:p.Val474Ala missense NM_001406785.1:c.1394T>C NP_001393714.1:p.Val465Ala missense NM_001406786.1:c.1385T>C NP_001393715.1:p.Val462Ala missense NM_001406787.1:c.1379T>C NP_001393716.1:p.Val460Ala missense NM_001406788.1:c.1226T>C NP_001393717.1:p.Val409Ala missense NM_001406789.1:c.1226T>C NP_001393718.1:p.Val409Ala missense NM_001406790.1:c.1226T>C NP_001393719.1:p.Val409Ala missense NM_001406791.1:c.1106T>C NP_001393720.1:p.Val369Ala missense NM_001406792.1:c.962T>C NP_001393721.1:p.Val321Ala missense NM_001406793.1:c.962T>C NP_001393722.1:p.Val321Ala missense NM_001406794.1:c.962T>C NP_001393723.1:p.Val321Ala missense NM_020629.2:c.2411T>C NP_065680.1:p.Val804Ala missense NM_020630.7:c.2411T>C NP_065681.1:p.Val804Ala missense NC_000010.11:g.43119549T>C NC_000010.10:g.43614997T>C NG_007489.1:g.47481T>C LRG_518:g.47481T>C LRG_518t1:c.2411T>C LRG_518p1:p.Val804Ala LRG_518t2:c.2411T>C LRG_518p2:p.Val804Ala - Protein change
- V804A, V550A, V672A, V759A, V321A, V409A, V474A, V505A, V761A, V369A, V460A, V658A, V708A, V462A, V465A, V562A, V629A, V716A
- Other names
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- Canonical SPDI
- NC_000010.11:43119548:T:C
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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 |
3592 | 3714 |
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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Sep 19, 2022 | RCV002726228.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 27, 2023 | RCV003167668.2 |
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
(Sep 19, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002999253.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Ala). 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. This variant disrupts the p.Val804 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8797874, 9452077, 10876191, 25501606). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is not present in population databases (gnomAD no frequency). (less)
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Uncertain significance
(Feb 27, 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: SCV003869137.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The p.V804A variant (also known as c.2411T>C), located in coding exon 14 of the RET gene, results from a T to C substitution at nucleotide … (more)
The p.V804A variant (also known as c.2411T>C), located in coding exon 14 of the RET gene, results from a T to C substitution at nucleotide position 2411. The valine at codon 804 is replaced by alanine, an amino acid with similar properties. Two other alterations at this position, p.V804M and p.V804L, have been designated as moderate risk mutations by the ATA (Wells SA et al. Thyroid. 2015 Jun;25:567-610). While this alteration has been classified as likely pathogenic in the literature, it has not been described in an individual with MEN2-related disease (Toledo RA et al. Endocr Relat Cancer. 2015 Feb;22:65-76; Margraf RL et al. Hum Mutat. 2022 Dec;43:1780-1794; Ambry internal data). 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)
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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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Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database. | Margraf RL | Human mutation | 2022 | PMID: 36251279 |
Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | Wells SA Jr | Thyroid : official journal of the American Thyroid Association | 2015 | PMID: 25810047 |
Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. | Basaran MN | Journal of endocrinological investigation | 2015 | PMID: 25501606 |
Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. | Toledo RA | Endocrine-related cancer | 2015 | PMID: 25425582 |
Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. | Feldman GL | Surgery | 2000 | PMID: 10876191 |
A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma. | Fattoruso O | Human mutation | 1998 | PMID: 9452077 |
Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)". | Fink M | International journal of cancer | 1996 | PMID: 8797874 |
Text-mined citations for rs1554819520 ...
HelpRecord last updated Sep 29, 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.