ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1189G>A (p.Val397Met)

gnomAD frequency: 0.00001  dbSNP: rs183729115
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000534092 SCV000658394 uncertain significance Multiple endocrine neoplasia, type 2 2024-10-30 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 397 of the RET protein (p.Val397Met). This variant is present in population databases (rs183729115, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22174939). ClinVar contains an entry for this variant (Variation ID: 477307). 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. 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 of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153730 SCV003843754 likely pathogenic Ovarian cancer 2022-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV004024396 SCV005028190 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-15 criteria provided, single submitter clinical testing The p.V397M variant (also known as c.1189G>A), located in coding exon 6 of the RET gene, results from a G to A substitution at nucleotide position 1189. The valine at codon 397 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a Chinese Hirschsprung disease patient; however, this patient was also found to carry a p.Y1062C alteration in RET that was confirmed to be in cis with the p.V397M alteration (So MT et al. PLoS One, 2011 Dec;6:e28986). This amino acid position is not well 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 RCV000534092 SCV005430322 uncertain significance Multiple endocrine neoplasia, type 2 2024-03-24 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 397 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Hirschsprung disease (PMID: 22174939). 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.
Fulgent Genetics, Fulgent Genetics RCV005034122 SCV005668334 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2024-04-14 criteria provided, single submitter clinical testing

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