Submissions for variant NM_001354604.2(MITF):c.1198C>T (p.Arg400Ter)

dbSNP: rs1464157509

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV001290158	SCV001478215	pathogenic	Waardenburg syndrome type 2A	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001543505	SCV001762118	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001544533	SCV001763579	pathogenic	Nonsyndromic genetic hearing loss	2021-07-15	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The c.877 C>T (p.Arg293*) in MITF gene is absent from population database (gnomAD) meeting PM2. This variant is predicted to generate a premature stop codon (more than 10% of the protein lost) applying to PVS1_Strong. It was reported in a family case with WS2 (PMID: 28690485). Besides, a family with autosomal dominant non-syndromic hearing loss exhibited this variant segregating in 5 affected relatives applyring to PP1_Strong (Internal data:Laboratory of Physiology and Genetics of Hearing). Considering all this information together: PM2, PVS1_S and PP1_Strong the c.877 C>T variant is classified as Pathogenic
GeneDx	RCV001543505	SCV002028588	pathogenic	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 127 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28690485, 31992338)
Invitae	RCV003770470	SCV004569530	pathogenic	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg293*) 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 individual(s) with autosomal dominant MITF-related conditions (PMID: 28690485, 34142234, 34997062). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 995923). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Deafness Molecular Diagnostic Center, Chinese PLA General Hospital	RCV001290158	SCV001763631	likely pathogenic	Waardenburg syndrome type 2A		no assertion criteria provided	case-control