ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1083C>A (p.Asn361Lys)
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.1083C>A (p.Asn361Lys)
Variation ID: 548864 Accession: VCV000548864.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43109050 (GRCh38) [ NCBI UCSC ] 10: 43604498 (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 Jul 15, 2018 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1083C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Asn361Lys missense NM_000323.2:c.1083C>A NP_000314.1:p.Asn361Lys missense NM_001355216.2:c.321C>A NP_001342145.1:p.Asn107Lys missense NM_001406743.1:c.1083C>A NP_001393672.1:p.Asn361Lys missense NM_001406744.1:c.1083C>A NP_001393673.1:p.Asn361Lys missense NM_001406759.1:c.1083C>A NP_001393688.1:p.Asn361Lys missense NM_001406760.1:c.1083C>A NP_001393689.1:p.Asn361Lys missense NM_001406761.1:c.954C>A NP_001393690.1:p.Asn318Lys missense NM_001406762.1:c.954C>A NP_001393691.1:p.Asn318Lys missense NM_001406763.1:c.1083C>A NP_001393692.1:p.Asn361Lys missense NM_001406764.1:c.954C>A NP_001393693.1:p.Asn318Lys missense NM_001406765.1:c.1083C>A NP_001393694.1:p.Asn361Lys missense NM_001406766.1:c.795C>A NP_001393695.1:p.Asn265Lys missense NM_001406767.1:c.795C>A NP_001393696.1:p.Asn265Lys missense NM_001406768.1:c.954C>A NP_001393697.1:p.Asn318Lys missense NM_001406770.1:c.795C>A NP_001393699.1:p.Asn265Lys missense NM_001406771.1:c.645C>A NP_001393700.1:p.Asn215Lys missense NM_001406773.1:c.645C>A NP_001393702.1:p.Asn215Lys missense NM_001406775.1:c.357C>A NP_001393704.1:p.Asn119Lys missense NM_001406776.1:c.357C>A NP_001393705.1:p.Asn119Lys missense NM_001406777.1:c.357C>A NP_001393706.1:p.Asn119Lys missense NM_001406778.1:c.357C>A NP_001393707.1:p.Asn119Lys missense NM_001406784.1:c.93C>A NP_001393713.1:p.Asn31Lys missense NM_020629.2:c.1083C>A NP_065680.1:p.Asn361Lys missense NM_020630.7:c.1083C>A NP_065681.1:p.Asn361Lys missense NC_000010.11:g.43109050C>A NC_000010.10:g.43604498C>A NG_007489.1:g.36982C>A LRG_518:g.36982C>A LRG_518t1:c.1083C>A LRG_518p1:p.Asn361Lys LRG_518t2:c.1083C>A LRG_518p2:p.Asn361Lys - Protein change
- N361K, N107K, N215K, N265K, N31K, N119K, N318K
- Other names
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- Canonical SPDI
- NC_000010.11:43109049:C:A
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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 | ||
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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
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. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3446 | 3566 |
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
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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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Feb 21, 2018 | RCV000663048.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000823028.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 24, 2023 | RCV001017228.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 15, 2021 | RCV001816663.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2022 | RCV002469239.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 17, 2023 | RCV003403528.4 |
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
(Feb 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786098.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Jan 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066755.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the RET gene demonstrated a sequence change, c.1083C>A, in exon 6 that results in an amino acid change, p.Asn361Lys. This sequence … (more)
DNA sequence analysis of the RET gene demonstrated a sequence change, c.1083C>A, in exon 6 that results in an amino acid change, p.Asn361Lys. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP rs770587835). The p.Asn361Lys change has been reported in an individual with Hirschsprung disease (PMID: 10790203). Functional studies have demonstrated that RET protein folding and cellular localization is impacted in the presence of this sequence change (PMID: 12915470, 26517685). The p.Asn361Lys change affects a poorly conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Asn361Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Asn361Lys change remains unknown at this time. (less)
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Uncertain significance
(Jul 26, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529910.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Dec 13, 2022)
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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: SCV002765582.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: abnormal protein folding and RET protein localization, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: abnormal protein folding and RET protein localization, but with ubiquitination levels close to wildtype (Kjaer et al., 2003; Jori et al., 2015); This variant is associated with the following publications: (PMID: 14633923, 12915470, 10790203, 26517685, 32179705) (less)
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Uncertain significance
(Jul 24, 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: SCV001178273.4
First in ClinVar: Mar 16, 2020 Last updated: Oct 28, 2023 |
Comment:
The p.N361K variant (also known as c.1083C>A), located in coding exon 6 of the RET gene, results from a C to A substitution at nucleotide … (more)
The p.N361K variant (also known as c.1083C>A), located in coding exon 6 of the RET gene, results from a C to A substitution at nucleotide position 1083. The asparagine at codon 361 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2 disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. (less)
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Uncertain significance
(May 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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RET-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119816.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The RET c.1083C>A variant is predicted to result in the amino acid substitution p.Asn361Lys. This variant has previously been reported in patients with variable and … (more)
The RET c.1083C>A variant is predicted to result in the amino acid substitution p.Asn361Lys. This variant has previously been reported in patients with variable and possibly RET-related phenotypes (including Hirschsprung, osteosarcoma, and Lynch syndrome), and some functional studies support its pathogenicity (Hofstra et al. 2000. PubMed ID: 10790203; Kjaer et al. 2003. PubMed ID: 12915470; Kovac et al. 2020. PubMed ID: 32179705; Jóri et al. 2015. PubMed ID: 26517685). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43604498-C-A) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/548864/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jan 18, 2024)
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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: SCV000963866.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 361 of the RET protein (p.Asn361Lys). … (more)
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 361 of the RET protein (p.Asn361Lys). This variant is present in population databases (rs770587835, gnomAD 0.004%). This missense change has been observed in individual(s) with Hirschsprung disease and/or osteosarcoma (PMID: 10790203, 32179705). ClinVar contains an entry for this variant (Variation ID: 548864). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 12915470, 26517685). 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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Germline RET variants underlie a subset of paediatric osteosarcoma. | Kovac M | Journal of medical genetics | 2021 | PMID: 32179705 |
Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients. | Jóri B | Oncotarget | 2015 | PMID: 26517685 |
Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET. | Kjaer S | Human molecular genetics | 2003 | PMID: 12915470 |
RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. | Hofstra RM | Human mutation | 2000 | PMID: 10790203 |
Text-mined citations for rs770587835 ...
HelpRecord last updated Apr 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.