ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.1352C>T (p.Thr451Met)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002508677 SCV002817930 uncertain significance not provided 2023-10-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV002571565 SCV003484744 uncertain significance Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 2022-08-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 344 of the MITF protein (p.Thr344Met). This variant is present in population databases (rs769488988, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MITF-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004690300 SCV005185733 uncertain significance not specified 2024-05-15 criteria provided, single submitter clinical testing Variant summary: MITF c.1031C>T (p.Thr344Met) results in a non-conservative amino acid change located in the Myc-type, basic helix-loop-helix (bHLH) domain (IPR011598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1031C>T in individuals affected with Waardenburg Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1810121). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences RCV003896209 SCV004711547 uncertain significance MITF-related disorder 2024-02-28 no assertion criteria provided clinical testing The MITF c.1031C>T variant is predicted to result in the amino acid substitution p.Thr344Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is not reported in ClinVar. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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