ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3148C>G (p.Arg1050Gly)

gnomAD frequency: 0.00001  dbSNP: rs767479170
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001018808 SCV001180087 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-19 criteria provided, single submitter clinical testing The p.R1050G variant (also known as c.3148C>G), located in coding exon 19 of the RET gene, results from a C to G substitution at nucleotide position 3148. The arginine at codon 1050 is replaced by glycine, an amino acid with dissimilar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001040336 SCV001203901 uncertain significance Multiple endocrine neoplasia, type 2 2024-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1050 of the RET protein (p.Arg1050Gly). This variant is present in population databases (rs767479170, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 822992). 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. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001195396 SCV001365746 uncertain significance not specified 2019-04-30 criteria provided, single submitter clinical testing The p.Arg1050Gly variant in RET has not been previously reported in individuals with RET-related cancers, but has been identified in 0.001% (1/113722) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3.
PreventionGenetics, part of Exact Sciences RCV004536052 SCV004117525 uncertain significance RET-related disorder 2023-07-25 criteria provided, single submitter clinical testing The RET c.3148C>G variant is predicted to result in the amino acid substitution p.Arg1050Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43622131-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV004569973 SCV005054206 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-01-17 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001040336 SCV005430410 uncertain significance Multiple endocrine neoplasia, type 2 2024-03-24 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 1050 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251432 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.

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