ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.666+5T>C

gnomAD frequency: 0.00004  dbSNP: rs374067688
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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 RCV000602988 SCV000711576 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The c.666+5T>C vari ant in MITF has been identified by our laboratory in one individual with hearing loss and their reportedly unaffected parent. Notably, a likely alternate etiolo gy was identified in the proband. The c.666+5C>T variant has also been identifie d in 0.01% (13/128806) of European chromosomes by gnomAD (http://gnomad.broadins titute.org). This variant is located in the 5' splice region. Computational tool s do not suggest an impact to splicing, but this information is not predictive e nough to rule out pathogenicity. In summary, while the clinical significance of the c.666+5T>C variant is uncertain, available data suggest that it is more like ly to be benign. ACMG/AMP criteria applied: BP4.
Sema4, Sema4 RCV002257852 SCV002536413 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-11 criteria provided, single submitter curation
GeneDx RCV003159139 SCV003853154 uncertain significance not provided 2022-09-30 criteria provided, single submitter clinical testing In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV003767426 SCV004576833 uncertain significance Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 2024-01-19 criteria provided, single submitter clinical testing This sequence change falls in intron 3 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 (rs374067688, gnomAD 0.009%). 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: 504813). 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.

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