ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2996C>T (p.Ala999Val)

gnomAD frequency: 0.00001  dbSNP: rs748288493
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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 RCV000654569 SCV000776463 uncertain significance Multiple endocrine neoplasia, type 2 2024-10-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 999 of the RET protein (p.Ala999Val). This variant is present in population databases (rs748288493, gnomAD 0.002%). 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: 543734). 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.
Ambry Genetics RCV002440387 SCV002750724 uncertain significance Hereditary cancer-predisposing syndrome 2024-08-23 criteria provided, single submitter clinical testing The p.A999V variant (also known as c.2996C>T), located in coding exon 18 of the RET gene, results from a C to T substitution at nucleotide position 2996. The alanine at codon 999 is replaced by valine, an amino acid with similar properties. 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.
Fulgent Genetics, Fulgent Genetics RCV002507128 SCV002806813 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2022-01-05 criteria provided, single submitter clinical testing

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