ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1183G>A (p.Val395Met)

gnomAD frequency: 0.00001  dbSNP: rs1452469572
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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 RCV001070874 SCV001236152 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 395 of the RET protein (p.Val395Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 30217742). ClinVar contains an entry for this variant (Variation ID: 863819). 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.
Ambry Genetics RCV002339346 SCV002637305 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-24 criteria provided, single submitter clinical testing The p.V395M variant (also known as c.1183G>A), located in coding exon 6 of the RET gene, results from a G to A substitution at nucleotide position 1183. The valine at codon 395 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in 1 individual in a cohort of patients with short-segment Hirschsprung disease and 0 controls. (Tang CS et al. Gastroenterology, 2018 12;155:1908-1922.e5). 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.
GeneDx RCV004590085 SCV005078038 uncertain significance not provided 2023-10-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed once in a cohort of Hirschsprung disease patients (Tang et al., 2018); This variant is associated with the following publications: (PMID: 14633923, 30217742)

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