ClinVar Genomic variation as it relates to human health

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. This variant is present in population databases (no rsID available, gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 545639). 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). For these reasons, this variant has been classified as Pathogenic.

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.

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.