Submissions for variant NM_016239.4(MYO15A):c.9408G>C (p.Trp3136Cys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317922	SCV004021139	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: MYO15A c.9408G>C (p.Trp3136Cys) results in a non-conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249302 control chromosomes (gnomAD). c.9408G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss (e.g. Wu_2019, Liu_2019, Lin_2021, Chen_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34974475, 34325055, 30682115, 31581539). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003443200	SCV004169592	likely pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Identified with a second variant (phase unknown) in additional unrelated patients with sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (Lin et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31581539, 34325055, 34974475, 30682115)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003443200	SCV004632432	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO15A protein function. This missense change has been observed in individuals with Deafness (PMID: 34974475). This variant is present in population databases (rs746969842, gnomAD 0.04%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 3136 of the MYO15A protein (p.Trp3136Cys).