ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)

dbSNP: rs876657699
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000218716 SCV000271397 pathogenic Rare genetic deafness 2016-01-12 criteria provided, single submitter clinical testing The p.Arg371X variant in MITF has been identified by our laboratory in one indiv idual with hearing loss, which is assumed to have occurred de novo. It has not been reported in large population studies. This nonsense variant leads to a pr emature termination codon at position 371 and is located 51 nucleotides from the end of the penultimate (second to last) exon. Therefore, this variant is expect ed to undergo nonsense mediated mRNA decay (NMD) (Holbrook 2004) resulting in a n absent protein. However, due to its close location to the penultimate intron it could escape NMD and leading to a truncated protein. Heterozygous loss of fu nction variants in the MITF gene are well described in individuals with Waardenb urg syndrome. In summary, the p.Arg371X variant meets the criteria to be classi fied as pathogenic for hearing loss in an autosomal dominant manner.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital RCV001290157 SCV001478214 pathogenic Waardenburg syndrome type 2A 2019-01-01 criteria provided, single submitter clinical testing
GeneDx RCV004719764 SCV005325770 likely pathogenic not provided 2023-10-31 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34142234, 27759048)
Labcorp Genetics (formerly Invitae), Labcorp RCV005222836 SCV005863462 pathogenic Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 2024-08-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg270*) in the MITF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MITF are known to be pathogenic (PMID: 8659547, 20127975). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Waardenburg syndrome (PMID: 27759048, 34142234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228363). For these reasons, this variant has been classified as Pathogenic.

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