Published functional studies demonstrate results similar to known MTC moderate-risk variants V804L and S891A, including transformation potential, tumor formation, low-level activating potential, a mild increase in kinase activity, and no invasion (Cranston et al., 2006); however, the clinical implications of these results are uncertain; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26678667, 25824727, 25810047, 19469690, 21479187, 17952863, 16469774, 25440022, 24699901, 27014708, 20301434, 24449662, 14633923, 34426522, 31510104, 32430905, 31605946, 32284345, 29590403)
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2497C>T (p.Arg833Cys)
Germline
Classification
Help
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.
(6)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(1)
Uncertain significance(5); Likely benign(1)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.2497C>T (p.Arg833Cys)
Variation ID: 24945 Accession: VCV000024945.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43119635 (GRCh38) [ NCBI UCSC ] 10: 43615083 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2497C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg833Cys missense NM_000323.2:c.2497C>T NP_000314.1:p.Arg833Cys missense NM_001355216.2:c.1735C>T NP_001342145.1:p.Arg579Cys missense NM_001406743.1:c.2497C>T NP_001393672.1:p.Arg833Cys missense NM_001406744.1:c.2497C>T NP_001393673.1:p.Arg833Cys missense NM_001406759.1:c.2497C>T NP_001393688.1:p.Arg833Cys missense NM_001406760.1:c.2497C>T NP_001393689.1:p.Arg833Cys missense NM_001406761.1:c.2368C>T NP_001393690.1:p.Arg790Cys missense NM_001406762.1:c.2368C>T NP_001393691.1:p.Arg790Cys missense NM_001406763.1:c.2362C>T NP_001393692.1:p.Arg788Cys missense NM_001406764.1:c.2368C>T NP_001393693.1:p.Arg790Cys missense NM_001406765.1:c.2362C>T NP_001393694.1:p.Arg788Cys missense NM_001406766.1:c.2209C>T NP_001393695.1:p.Arg737Cys missense NM_001406767.1:c.2209C>T NP_001393696.1:p.Arg737Cys missense NM_001406768.1:c.2233C>T NP_001393697.1:p.Arg745Cys missense NM_001406769.1:c.2101C>T NP_001393698.1:p.Arg701Cys missense NM_001406770.1:c.2209C>T NP_001393699.1:p.Arg737Cys missense NM_001406771.1:c.2059C>T NP_001393700.1:p.Arg687Cys missense NM_001406772.1:c.2101C>T NP_001393701.1:p.Arg701Cys missense NM_001406773.1:c.2059C>T NP_001393702.1:p.Arg687Cys missense NM_001406774.1:c.1972C>T NP_001393703.1:p.Arg658Cys missense NM_001406775.1:c.1771C>T NP_001393704.1:p.Arg591Cys missense NM_001406776.1:c.1771C>T NP_001393705.1:p.Arg591Cys missense NM_001406777.1:c.1771C>T NP_001393706.1:p.Arg591Cys missense NM_001406778.1:c.1771C>T NP_001393707.1:p.Arg591Cys missense NM_001406779.1:c.1600C>T NP_001393708.1:p.Arg534Cys missense NM_001406780.1:c.1600C>T NP_001393709.1:p.Arg534Cys missense NM_001406781.1:c.1600C>T NP_001393710.1:p.Arg534Cys missense NM_001406782.1:c.1600C>T NP_001393711.1:p.Arg534Cys missense NM_001406783.1:c.1471C>T NP_001393712.1:p.Arg491Cys missense NM_001406784.1:c.1507C>T NP_001393713.1:p.Arg503Cys missense NM_001406785.1:c.1480C>T NP_001393714.1:p.Arg494Cys missense NM_001406786.1:c.1471C>T NP_001393715.1:p.Arg491Cys missense NM_001406787.1:c.1465C>T NP_001393716.1:p.Arg489Cys missense NM_001406788.1:c.1312C>T NP_001393717.1:p.Arg438Cys missense NM_001406789.1:c.1312C>T NP_001393718.1:p.Arg438Cys missense NM_001406790.1:c.1312C>T NP_001393719.1:p.Arg438Cys missense NM_001406791.1:c.1192C>T NP_001393720.1:p.Arg398Cys missense NM_001406792.1:c.1048C>T NP_001393721.1:p.Arg350Cys missense NM_001406793.1:c.1048C>T NP_001393722.1:p.Arg350Cys missense NM_001406794.1:c.1048C>T NP_001393723.1:p.Arg350Cys missense NM_020629.2:c.2497C>T NP_065680.1:p.Arg833Cys missense NM_020630.7:c.2497C>T NP_065681.1:p.Arg833Cys missense NC_000010.11:g.43119635C>T NC_000010.10:g.43615083C>T NG_007489.1:g.47567C>T LRG_518:g.47567C>T LRG_518t1:c.2497C>T LRG_518p1:p.Arg833Cys LRG_518t2:c.2497C>T LRG_518p2:p.Arg833Cys - Protein change
- R579C, R398C, R687C, R737C, R745C, R788C, R790C, R350C, R494C, R503C, R591C, R658C, R534C, R701C, R438C, R489C, R491C
- Other names
- -
- Canonical SPDI
- NC_000010.11:43119634:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3595 | 3717 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 19, 2022 | RCV000478761.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 18, 2023 | RCV000662806.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 1, 2024 | RCV000529442.16 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 16, 2023 | RCV000567481.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 24, 2024 | RCV004566753.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Oct 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785639.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
|
|
|
Uncertain significance
(Aug 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568558.7
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate results similar to known MTC moderate-risk variants V804L and S891A, including transformation potential, tumor formation, low-level activating potential, a mild increase … (more)
Published functional studies demonstrate results similar to known MTC moderate-risk variants V804L and S891A, including transformation potential, tumor formation, low-level activating potential, a mild increase in kinase activity, and no invasion (Cranston et al., 2006); however, the clinical implications of these results are uncertain; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26678667, 25824727, 25810047, 19469690, 21479187, 17952863, 16469774, 25440022, 24699901, 27014708, 20301434, 24449662, 14633923, 34426522, 31510104, 32430905, 31605946, 32284345, 29590403) (less)
|
|
|
Uncertain significance
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018501.1
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.
|
|
|
Uncertain significance
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000658454.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 833 of the RET protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 833 of the RET protein (p.Arg833Cys). This variant is present in population databases (rs377767422, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of RET-related conditions (PMID: 16469774, 25440022, 32430905). ClinVar contains an entry for this variant (Variation ID: 24945). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 16469774). 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)
|
|
|
Likely benign
(Feb 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000674804.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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)
|
|
|
Uncertain significance
(Mar 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005054172.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
Comment:
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.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 833 of the RET protein (p.Arg833Cys). This variant is present in population databases (rs377767422, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of RET-related conditions (PMID: 16469774, 25440022, 32430905). ClinVar contains an entry for this variant (Variation ID: 24945). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 16469774). 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.
Comment:
This alteration is classified as likely 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.
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. |
Comment:
Published functional studies demonstrate results similar to known MTC moderate-risk variants V804L and S891A, including transformation potential, tumor formation, low-level activating potential, a mild increase in kinase activity, and no invasion (Cranston et al., 2006); however, the clinical implications of these results are uncertain; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26678667, 25824727, 25810047, 19469690, 21479187, 17952863, 16469774, 25440022, 24699901, 27014708, 20301434, 24449662, 14633923, 34426522, 31510104, 32430905, 31605946, 32284345, 29590403)
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.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 833 of the RET protein (p.Arg833Cys). This variant is present in population databases (rs377767422, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of RET-related conditions (PMID: 16469774, 25440022, 32430905). ClinVar contains an entry for this variant (Variation ID: 24945). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 16469774). 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.
Comment:
This alteration is classified as likely 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort. | Mariathasan S | Clinical endocrinology | 2020 | PMID: 32430905 |
| In silico analysis of RET variants in medullary thyroid cancer: from the computer to the bedside. | Heineman TE | Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2015 | PMID: 25733075 |
| Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? | Romei C | Clinical endocrinology | 2015 | PMID: 25440022 |
| RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. | Krampitz GW | Cancer | 2014 | PMID: 24699901 |
| Medullary thyroid cancer: management guidelines of the American Thyroid Association. | American Thyroid Association Guidelines Task Force | Thyroid : official journal of the American Thyroid Association | 2009 | PMID: 19469690 |
| A novel activating mutation in the RET tyrosine kinase domain mediates neoplastic transformation. | Cranston A | Molecular endocrinology (Baltimore, Md.) | 2006 | PMID: 16469774 |
Text-mined citations for rs377767422 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.