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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RET-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 819 of the RET protein (p.Ser819Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2457C>G (p.Ser819Arg)
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.
(2)
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.
Uncertain significance
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.2457C>G (p.Ser819Arg)
Variation ID: 1481838 Accession: VCV001481838.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119595 (GRCh38) [ NCBI UCSC ] 10: 43615043 (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 Mar 28, 2022 May 1, 2024 May 9, 2021 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2457C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Ser819Arg missense NM_000323.2:c.2457C>G NP_000314.1:p.Ser819Arg missense NM_001355216.2:c.1695C>G NP_001342145.1:p.Ser565Arg missense NM_001406743.1:c.2457C>G NP_001393672.1:p.Ser819Arg missense NM_001406744.1:c.2457C>G NP_001393673.1:p.Ser819Arg missense NM_001406759.1:c.2457C>G NP_001393688.1:p.Ser819Arg missense NM_001406760.1:c.2457C>G NP_001393689.1:p.Ser819Arg missense NM_001406761.1:c.2328C>G NP_001393690.1:p.Ser776Arg missense NM_001406762.1:c.2328C>G NP_001393691.1:p.Ser776Arg missense NM_001406763.1:c.2322C>G NP_001393692.1:p.Ser774Arg missense NM_001406764.1:c.2328C>G NP_001393693.1:p.Ser776Arg missense NM_001406765.1:c.2322C>G NP_001393694.1:p.Ser774Arg missense NM_001406766.1:c.2169C>G NP_001393695.1:p.Ser723Arg missense NM_001406767.1:c.2169C>G NP_001393696.1:p.Ser723Arg missense NM_001406768.1:c.2193C>G NP_001393697.1:p.Ser731Arg missense NM_001406769.1:c.2061C>G NP_001393698.1:p.Ser687Arg missense NM_001406770.1:c.2169C>G NP_001393699.1:p.Ser723Arg missense NM_001406771.1:c.2019C>G NP_001393700.1:p.Ser673Arg missense NM_001406772.1:c.2061C>G NP_001393701.1:p.Ser687Arg missense NM_001406773.1:c.2019C>G NP_001393702.1:p.Ser673Arg missense NM_001406774.1:c.1932C>G NP_001393703.1:p.Ser644Arg missense NM_001406775.1:c.1731C>G NP_001393704.1:p.Ser577Arg missense NM_001406776.1:c.1731C>G NP_001393705.1:p.Ser577Arg missense NM_001406777.1:c.1731C>G NP_001393706.1:p.Ser577Arg missense NM_001406778.1:c.1731C>G NP_001393707.1:p.Ser577Arg missense NM_001406779.1:c.1560C>G NP_001393708.1:p.Ser520Arg missense NM_001406780.1:c.1560C>G NP_001393709.1:p.Ser520Arg missense NM_001406781.1:c.1560C>G NP_001393710.1:p.Ser520Arg missense NM_001406782.1:c.1560C>G NP_001393711.1:p.Ser520Arg missense NM_001406783.1:c.1431C>G NP_001393712.1:p.Ser477Arg missense NM_001406784.1:c.1467C>G NP_001393713.1:p.Ser489Arg missense NM_001406785.1:c.1440C>G NP_001393714.1:p.Ser480Arg missense NM_001406786.1:c.1431C>G NP_001393715.1:p.Ser477Arg missense NM_001406787.1:c.1425C>G NP_001393716.1:p.Ser475Arg missense NM_001406788.1:c.1272C>G NP_001393717.1:p.Ser424Arg missense NM_001406789.1:c.1272C>G NP_001393718.1:p.Ser424Arg missense NM_001406790.1:c.1272C>G NP_001393719.1:p.Ser424Arg missense NM_001406791.1:c.1152C>G NP_001393720.1:p.Ser384Arg missense NM_001406792.1:c.1008C>G NP_001393721.1:p.Ser336Arg missense NM_001406793.1:c.1008C>G NP_001393722.1:p.Ser336Arg missense NM_001406794.1:c.1008C>G NP_001393723.1:p.Ser336Arg missense NM_020629.2:c.2457C>G NP_065680.1:p.Ser819Arg missense NM_020630.7:c.2457C>G NP_065681.1:p.Ser819Arg missense NC_000010.11:g.43119595C>G NC_000010.10:g.43615043C>G NG_007489.1:g.47527C>G LRG_518:g.47527C>G LRG_518t1:c.2457C>G LRG_518p1:p.Ser819Arg LRG_518t2:c.2457C>G LRG_518p2:p.Ser819Arg - Protein change
- S819R, S565R, S520R, S577R, S644R, S731R, S776R, S477R, S489R, S673R, S687R, S475R, S774R, S336R, S384R, S424R, S480R, S723R
- Other names
- -
- Canonical SPDI
- NC_000010.11:43119594: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
Help
The frequency of the allele represented by this VCV record.
- -
- 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
|
Apr 28, 2021 | RCV002025033.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 9, 2021 | RCV002442988.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002270580.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RET-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 819 of the RET protein (p.Ser819Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. (less)
|
|
|
Uncertain significance
(May 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002732222.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S819R variant (also known as c.2457C>G), located in coding exon 14 of the RET gene, results from a C to G substitution at nucleotide … (more)
The p.S819R variant (also known as c.2457C>G), located in coding exon 14 of the RET gene, results from a C to G substitution at nucleotide position 2457. The serine at codon 819 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
The p.S819R variant (also known as c.2457C>G), located in coding exon 14 of the RET gene, results from a C to G substitution at nucleotide position 2457. The serine at codon 819 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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:
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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RET-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 819 of the RET protein (p.Ser819Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine.
Comment:
The p.S819R variant (also known as c.2457C>G), located in coding exon 14 of the RET gene, results from a C to G substitution at nucleotide position 2457. The serine at codon 819 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| There 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 rs375322585 ...
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 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.