Submissions for variant NM_000260.4(MYO7A):c.1903T>C (p.Cys635Arg)

dbSNP: rs797044514

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001347350	SCV000205643	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	The p.Cys635Arg variant in MYO7A has been reported in 5 homozygous individuals with hearing loss and retinal dysfunction (Neuhaus 2017 PMID: 28944237, Kletke 2017 PMID: 27743452, LMM data, GeneDx pers. comm.). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 179146). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347350	SCV001541606	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 635 of the MYO7A protein (p.Cys635Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Usher syndrome type 1 (PMID: 27743452). ClinVar contains an entry for this variant (Variation ID: 179146). 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. 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	RCV001347350	SCV001819255	likely pathogenic	not provided	2019-12-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28944237, 27743452)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689630	SCV005185619	likely pathogenic	Usher syndrome	2024-05-17	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.1903T>C (p.Cys635Arg) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 155584 control chromosomes. c.1903T>C has been reported in the literature in homozygous individuals affected with Autosomal Recessive Usher Syndrome (Kletke_2017, Neuhaus_2017). These data indicate that the variant is 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: 27743452, 28944237). ClinVar contains an entry for this variant (Variation ID: 179146). Based on the evidence outlined above, the variant was classified as likely pathogenic.