Submissions for variant NM_001354604.2(MITF):c.1157G>A (p.Arg386Gln)

gnomAD frequency: 0.00004  dbSNP: rs775320252

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002284452	SCV002010535	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002259067	SCV002536420	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	curation
GeneDx	RCV002284452	SCV002574613	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549995	SCV003010912	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 279 of the MITF protein (p.Arg279Gln). This variant is present in population databases (rs775320252, gnomAD 0.004%). 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: 809506). 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 not expected to disrupt MITF protein function with a negative 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.
Ambry Genetics	RCV002259067	SCV005444995	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-18	criteria provided, single submitter	clinical testing	The p.R279Q variant (also known as c.836G>A), located in coding exon 8 of the MITF gene, results from a G to A substitution at nucleotide position 836. The arginine at codon 279 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004746192	SCV005351704	uncertain significance	MITF-related disorder	2024-08-24	no assertion criteria provided	clinical testing	The MITF c.836G>A variant is predicted to result in the amino acid substitution p.Arg279Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD, including over 50 heterozygous individuals in the larger gnomADv4.1.1 dataset (https://gnomad.broadinstitute.org/variant/3-69959398-G-A?dataset=gnomad_r4). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.