Submissions for variant NM_001354604.2(MITF):c.1179+4C>T

gnomAD frequency: 0.00003  dbSNP: rs749869303

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615376	SCV000731337	uncertain significance	not specified	2017-01-19	criteria provided, single submitter	clinical testing	The c.1161+4C>T variant in MITF has not been previously reported in individuals with hearing loss. It has been identified in 23/65822 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs74 9869303). Although this variant has been seen in the general population, its fre quency is not high enough to rule out a pathogenic role. This variant is locate d in the 5' splice region. Computational tools do not suggest an impact to splic ing. However, this information is not predictive enough to rule out pathogenicit y. In summary, the clinical significance of the c.1161+4C>T variant is uncertain .
GeneDx	RCV001591370	SCV001824282	likely benign	not provided	2018-06-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000615376	SCV002550868	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531674	SCV003498475	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 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 (rs749869303, gnomAD 0.03%). 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: 517197). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003230270	SCV003928103	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 8	2023-04-03	criteria provided, single submitter	clinical testing	The MITF c.1161+4C>T intronic change results in a C to T substitution at the +4 position of intron 9 of the MITF gene. Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. This variant has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). To our knowledge, this variant has not been reported in individuals with melanoma and renal cell carcinoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003965293	SCV004780387	likely benign	MITF-related disorder	2021-12-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).