The MITF gene has been associated with autosomal dominant Waardenburg syndrome type 2 using the ClinGen Clinical Validity Framework as of 6/14/2017. This association was made using case-level data only. At least 8 variants (missense, in-frame indel, nonsense, stoploss, frameshift, splice, and large deletion) have been reported in humans. MITF was first associated with this disease in humans as early as 1994 (Tassabehji et al.). Association is seen in at least 8 probands in 4 publications (7874167, 23512835, 27759048, 28356565). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is likely haploinsufficiency. This gene-disease association is supported by numerous animal models (Steingrimsson 1994, Hodgkinson 1998, Chen 2016), as well as biochemical functional assays (Grill 2013, Sun 2017). In summary, MITF is definitively associated with autosomal dominant Waardenburg syndrome type 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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