ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2449C>T (p.Arg817Cys)
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.2449C>T (p.Arg817Cys)
Variation ID: 136111 Accession: VCV000136111.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119587 (GRCh38) [ NCBI UCSC ] 10: 43615035 (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 6, 2017 May 1, 2024 Nov 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2449C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg817Cys missense NM_000323.2:c.2449C>T NP_000314.1:p.Arg817Cys missense NM_001355216.2:c.1687C>T NP_001342145.1:p.Arg563Cys missense NM_001406743.1:c.2449C>T NP_001393672.1:p.Arg817Cys missense NM_001406744.1:c.2449C>T NP_001393673.1:p.Arg817Cys missense NM_001406759.1:c.2449C>T NP_001393688.1:p.Arg817Cys missense NM_001406760.1:c.2449C>T NP_001393689.1:p.Arg817Cys missense NM_001406761.1:c.2320C>T NP_001393690.1:p.Arg774Cys missense NM_001406762.1:c.2320C>T NP_001393691.1:p.Arg774Cys missense NM_001406763.1:c.2314C>T NP_001393692.1:p.Arg772Cys missense NM_001406764.1:c.2320C>T NP_001393693.1:p.Arg774Cys missense NM_001406765.1:c.2314C>T NP_001393694.1:p.Arg772Cys missense NM_001406766.1:c.2161C>T NP_001393695.1:p.Arg721Cys missense NM_001406767.1:c.2161C>T NP_001393696.1:p.Arg721Cys missense NM_001406768.1:c.2185C>T NP_001393697.1:p.Arg729Cys missense NM_001406769.1:c.2053C>T NP_001393698.1:p.Arg685Cys missense NM_001406770.1:c.2161C>T NP_001393699.1:p.Arg721Cys missense NM_001406771.1:c.2011C>T NP_001393700.1:p.Arg671Cys missense NM_001406772.1:c.2053C>T NP_001393701.1:p.Arg685Cys missense NM_001406773.1:c.2011C>T NP_001393702.1:p.Arg671Cys missense NM_001406774.1:c.1924C>T NP_001393703.1:p.Arg642Cys missense NM_001406775.1:c.1723C>T NP_001393704.1:p.Arg575Cys missense NM_001406776.1:c.1723C>T NP_001393705.1:p.Arg575Cys missense NM_001406777.1:c.1723C>T NP_001393706.1:p.Arg575Cys missense NM_001406778.1:c.1723C>T NP_001393707.1:p.Arg575Cys missense NM_001406779.1:c.1552C>T NP_001393708.1:p.Arg518Cys missense NM_001406780.1:c.1552C>T NP_001393709.1:p.Arg518Cys missense NM_001406781.1:c.1552C>T NP_001393710.1:p.Arg518Cys missense NM_001406782.1:c.1552C>T NP_001393711.1:p.Arg518Cys missense NM_001406783.1:c.1423C>T NP_001393712.1:p.Arg475Cys missense NM_001406784.1:c.1459C>T NP_001393713.1:p.Arg487Cys missense NM_001406785.1:c.1432C>T NP_001393714.1:p.Arg478Cys missense NM_001406786.1:c.1423C>T NP_001393715.1:p.Arg475Cys missense NM_001406787.1:c.1417C>T NP_001393716.1:p.Arg473Cys missense NM_001406788.1:c.1264C>T NP_001393717.1:p.Arg422Cys missense NM_001406789.1:c.1264C>T NP_001393718.1:p.Arg422Cys missense NM_001406790.1:c.1264C>T NP_001393719.1:p.Arg422Cys missense NM_001406791.1:c.1144C>T NP_001393720.1:p.Arg382Cys missense NM_001406792.1:c.1000C>T NP_001393721.1:p.Arg334Cys missense NM_001406793.1:c.1000C>T NP_001393722.1:p.Arg334Cys missense NM_001406794.1:c.1000C>T NP_001393723.1:p.Arg334Cys missense NM_020629.2:c.2449C>T NP_065680.1:p.Arg817Cys missense NM_020630.7:c.2449C>T NP_065681.1:p.Arg817Cys missense NC_000010.11:g.43119587C>T NC_000010.10:g.43615035C>T NG_007489.1:g.47519C>T LRG_518:g.47519C>T LRG_518t1:c.2449C>T LRG_518p1:p.Arg817Cys LRG_518t2:c.2449C>T LRG_518p2:p.Arg817Cys - Protein change
- R817C, R563C, R487C, R642C, R671C, R721C, R382C, R422C, R478C, R518C, R772C, R334C, R475C, R575C, R473C, R685C, R729C, R774C
- Other names
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- Canonical SPDI
- NC_000010.11:43119586:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
Help
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 |
3523 | 3643 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2023 | RCV000123311.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000409506.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 20, 2016 | RCV000411874.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 10, 2023 | RCV000414497.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 21, 2022 | RCV001015577.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2023 | RCV002466440.2 |
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
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
(Jun 21, 2022)
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criteria provided, single submitter
Method: research
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Hirschsprung disease, susceptibility to, 1
Affected status: no, yes
Allele origin:
paternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV002762740.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
ACMG codes:PM1_Moderate, PP3_Supporting
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Brain imaging abnormality (present) , Seizure (present) , Congenital blindness (present) , Dysphagia (present) , Cerebral palsy (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Aganglionic megacolon (present)
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Uncertain significance
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018490.1
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.
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Uncertain significance
(Nov 10, 2023)
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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: SCV000490770.7
First in ClinVar: Jan 09, 2017 Last updated: Nov 25, 2023 |
Comment:
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; … (more)
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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24336963, 29625052, 14633923) (less)
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Uncertain significance
(Jun 23, 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: SCV004206712.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jun 27, 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: SCV000166618.10
First in ClinVar: Jun 16, 2014 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 29625052). 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. ClinVar contains an entry for this variant (Variation ID: 136111). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (rs142318626, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 817 of the RET protein (p.Arg817Cys). (less)
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Uncertain significance
(May 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489843.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(May 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489844.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain Significance
(Nov 30, 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: SCV004838671.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with cysteine at codon 817 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 817 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant did not cause ectopic activation of RET kinase activity in a cellular assay (PMID: 29625052). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/244670 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: 4
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Uncertain significance
(Feb 21, 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: SCV001176424.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.2449C>T (p.R817C) alteration is located in exon 14 (coding exon 14) of the RET gene. This alteration results from a C to T substitution … (more)
The c.2449C>T (p.R817C) alteration is located in exon 14 (coding exon 14) of the RET gene. This alteration results from a C to T substitution at nucleotide position 2449, causing the arginine (R) at amino acid position 817 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, 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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Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach. | George Priya Doss C | Molecular bioSystems | 2014 | PMID: 24336963 |
Text-mined citations for rs142318626 ...
HelpRecord last updated May 12, 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.