ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.415G>A (p.Val139Ile)

gnomAD frequency: 0.00002  dbSNP: rs371031432
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001543129 SCV001761649 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 8 2021-07-08 criteria provided, single submitter clinical testing The MITF c.415G>A (p.Val139Ile) missense change has a maximum population frequency of 0.0080% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/3-69987033-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting.
GeneDx RCV001773769 SCV002002513 uncertain significance not provided 2022-07-27 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 RCV003771665 SCV004589013 uncertain significance Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 32 of the MITF protein (p.Val32Ile). This variant is present in population databases (rs371031432, gnomAD 0.008%). 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: 1184722). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MITF protein function. 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.
PreventionGenetics, part of Exact Sciences RCV004746420 SCV005342524 uncertain significance MITF-related disorder 2024-06-17 no assertion criteria provided clinical testing The MITF c.93+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. In an alternate transcript (NM_001354604.2), this variant is also known as c.415G>A (p.Val139Ile). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1184722/). 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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