ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.823C>A (p.Leu275Ile)

gnomAD frequency: 0.00001  dbSNP: rs763339433
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001765217 SCV001991925 uncertain significance not provided 2021-04-28 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 RCV002540238 SCV002936003 uncertain significance Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 2022-04-09 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 168 of the MITF protein (p.Leu168Ile). This variant is present in population databases (rs763339433, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MITF-related conditions. ClinVar contains an entry for this variant (Variation ID: 1305042). 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. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV003339730 SCV004048098 uncertain significance Oculocutaneous albinism type 4 criteria provided, single submitter clinical testing The missense variant p.L275I in MITF (NM_001354604.2) has been reported to clinvar as Uncertain Significance. The p.L275I variant is observed in 2/30,610 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between leucine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Leu168Ile in MITF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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