ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2245A>G (p.Arg749Gly)

gnomAD frequency: 0.00001  dbSNP: rs1210164099
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001344497 SCV001538556 uncertain significance Multiple endocrine neoplasia, type 2 2022-08-22 criteria provided, single submitter clinical testing 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1040791). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 749 of the RET protein (p.Arg749Gly).
Ambry Genetics RCV002419017 SCV002725513 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-18 criteria provided, single submitter clinical testing The p.R749G variant (also known as c.2245A>G), located in coding exon 12 of the RET gene, results from an A to G substitution at nucleotide position 2245. The arginine at codon 749 is replaced by glycine, an amino acid with dissimilar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV001344497 SCV004839288 uncertain significance Multiple endocrine neoplasia, type 2 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 749 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has not been identified 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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