Submissions for variant NM_001354604.2(MITF):c.1072G>A (p.Val358Met)

dbSNP: rs1271000541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659866	SCV000781748	uncertain significance	Waardenburg syndrome type 2A	2016-11-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000659866	SCV000845306	uncertain significance	Waardenburg syndrome type 2A	2018-08-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195616	SCV001366015	uncertain significance	not specified	2019-06-07	criteria provided, single submitter	clinical testing	The p.Val251Met variant in MITF has been previously identified in one individual with hearing loss and heterochromia iridium by our laboratory and was absent from large population studies. This variant has been reported in ClinVar (Variation ID 547535). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val251Met variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP4.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796267	SCV005417610	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8; Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV005223089	SCV005868694	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2024-10-03	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 251 of the MITF protein (p.Val251Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Waardenburg syndrome (PMID: 30978479). ClinVar contains an entry for this variant (Variation ID: 547535). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MITF protein function with a positive predictive value of 80%. 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	RCV003411566	SCV004111880	likely pathogenic	MITF-related disorder	2024-09-26	no assertion criteria provided	clinical testing	The MITF c.751G>A variant is predicted to result in the amino acid substitution p.Val251Met. This variant was reported in a patient with Waardenburg syndrome (Minami et al. 2019. PubMed ID: 30978479) and occurred de novo in a patient with bilateral sensorineural hearing loss (PreventionGenetics, internal data). Additionally, this variant was identified in an individual with congenital deafness and iris heterochromia (Table S2, Abolhassani et al. 2024. PubMed ID: 38374194). This variant has not been reported in a large population database, indicating it is rare. We interpret this variant as likely pathogenic.