Submissions for variant NM_001354604.2(MITF):c.1039C>G (p.Arg347Gly)

dbSNP: rs1559751245

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001756113	SCV001988388	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in siblings with nonsyndromic hearing loss and their unaffected mother in the published literature (Zhang et al., 2018); This variant is associated with the following publications: (PMID: 29484430, 30394532)
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV004698346	SCV005199929	pathogenic	Waardenburg syndrome type 2A	2024-08-20	criteria provided, single submitter	research	An autosomal dominnat, pathogenic variant based on Deafness Variation Database, ClinVar and PMID: 29484430. It was detected in an individual with WS2 and profound deafness.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005223085	SCV005863861	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2024-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 240 of the MITF protein (p.Arg240Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MITF-related conditions (PMID: 29484430, 30394532, 33724713). This variant is also known as p.Arg341Gly. ClinVar contains an entry for this variant (Variation ID: 545117). 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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000721954	SCV000763161	likely pathogenic	Tietz syndrome; Waardenburg syndrome type 2A	2018-05-15	no assertion criteria provided	research