Submissions for variant NM_001354604.2(MITF):c.355-1062G>C

gnomAD frequency: 0.00001  dbSNP: rs1236436555

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002534250	SCV003525336	pathogenic	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2022-05-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 30117279). ClinVar contains an entry for this variant (Variation ID: 545639). This variant has been observed in individuals with clinical features of autosomal dominant Waardenburg Syndrome, type 2A (PMID: 21373256, 30117279). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change falls in intron 1 of the MITF gene. It does not directly change the encoded amino acid sequence of the MITF protein. It affects a nucleotide within the consensus splice site.
King Laboratory, University of Washington	RCV003155262	SCV003844122	likely pathogenic	Waardenburg syndrome type 2A	2023-02-28	criteria provided, single submitter	research	This variant occurred in heterozygosity in an individual with Waardenburg syndrome including heterochromia iridis and bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no other history of hearing loss. This variant is a single base pair substitution near the beginning of the first MITF intron. It is at a site that is completely conserved and is predicted to disrupt the donor splice site of MITF isoform M exon 1. At chr3:69985911, the sequence change is CAG|gtgaga > CAGgtgaca, NNSPLICE is 0.93 and 0.45 and MaxEnt is 9.22 and 5.49 for reference and mutant sequences, respectively. At the transcript level, the predicted consequence of this splice variant would be loss of expression of MITF isoform M from the mutant allele. As of January 2023, this variant has been reported previously in an individual with hearing loss (Waardenburg Type 2) and is currently classified as likely pathogenic on ClinVar, and it is found in 1 heterozygous individual on gnomAD. Based on the prediction that this variant leads to a splicing error and a truncated protein, previous classification as likely pathogenic, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
Institute for Human Genetics, University Medical Center Freiburg	RCV000722130	SCV000777908	likely pathogenic	Waardenburg syndrome type 2		no assertion criteria provided	research	Our work describes a unique depigmentation phenotype in an Argentinean boy due to a MITF mutation. Our index patient was born to consanguineous parents (siblings) and thus is a homozygous carrier of the intronic mutation NM_000248.3:c.33+5G>C in the recognition context of the splice donor site specific to the melanocyte-specific M transcript variant of MITF. Several further family members are heterozygous carriers and presented a Waardenburg syndrome type 2A phenotype with typical variable expressivity.