Submissions for variant NM_001354604.2(MITF):c.1031C>T (p.Pro344Leu)

gnomAD frequency: 0.00001  dbSNP: rs756923654

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Nemer Genomics and Translation Biomedicine Lab, American University of Beirut	RCV000984522	SCV001035077	uncertain significance	Nonsyndromic Deafness		criteria provided, single submitter	research	This is the first description of a non-syndromic hearing loss recessive familial case with a homozygous missense mutation in MITF. The missense mutation p.P338L lies within the bHLH domain of the protein with in silico analysis predicting functional defects of the protein. The mutation segregates with the phenotype observed in the two affected probands which carry the homozygous form of the mutant allele.
Fulgent Genetics, Fulgent Genetics	RCV002505495	SCV002815452	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8; Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness	2021-11-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549628	SCV003270322	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 237 of the MITF protein (p.Pro237Leu). This variant is present in population databases (rs756923654, gnomAD 0.002%). This missense change has been observed in individual(s) with hearing loss (PMID: 31898538). This variant is also known as c.1013C>T. ClinVar contains an entry for this variant (Variation ID: 800541). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx	RCV001356827	SCV003930590	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Observed in the homozygous state in two sisters with non-syndromic hearing loss, co-occurring with variants in MYO15A, MYO7A, and MYH14 (Khalil et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1013C>T; p.(P338L); This variant is associated with the following publications: (PMID: 31898538)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356827	SCV001552096	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MITF p.Pro175Leu variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs756923654) and in control databases in 3 of 282462 chromosomes at a frequency of 0.000011 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7200 chromosomes (freq: 0.000139) and European (non-Finnish) in 2 of 128908 chromosomes (freq: 0.000016); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Pro175 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Pro175Leu variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, only 1 of 4 in silico or computational prediction software programs (NNSPLICE) predict a greater than 10% decrease in splicing at the canonical 5' splice site; the other 3 splicing prediction programs do not predict a difference (SpliceSiteFinder, MaxEntScan, GeneSplicer). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.