Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000779081 | SCV000915557 | likely pathogenic | MYO7A-Related Disorders | 2018-08-16 | criteria provided, single submitter | clinical testing | Variants in the MYO7A gene are associated with MYO7A-related disorders, including both autosomal dominant and recessive nonsydromic hearing loss and Usher syndrome. The MYO7A c.5434G>A (p.Glu1812Lys) missense variant has been reported at least three studies in which it is found in a homozygous state in four individuals from three families with Usher syndrome (Roux et al. 2011; Glöckle et al. 2014; Riahi et al, 2015). In two families, the parents of the affected individuals were each identified as being heterozygous for the p.Glu1812Lys variant. Control data are not available for this variant, which is reported at a frequency of 0.000237 in the African American population of the Exome Sequencing Project, however this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. Wu et al. (2011) report on the crystal structure of the MyTH4-FREM domains of MYO7A and note that the p.Glu1812Lys variant occurs in the c-terminal region of the domain, where the authors suggest it is likely to disrupt folding. Based on the evidence, the p.Glu1812Lys variant is classified as likely pathogenic for MYO7A-related disorders. Note: While this variant has not been reported in conjunction with autosomal dominant nonsyndromic hearing loss, disease risk cannot be ruled out. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV001383418 | SCV001582559 | pathogenic | not provided | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1812 of the MYO7A protein (p.Glu1812Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Usher syndrome (PMID: 21436283, 23591405, 25798947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632175). 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 MYO7A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| University of Washington Center for Mendelian Genomics, |
RCV001291102 | SCV001479468 | likely pathogenic | Hearing loss, autosomal recessive | no assertion criteria provided | research |