Submissions for variant NM_000260.4(MYO7A):c.2002C>T (p.Arg668Cys)

gnomAD frequency: 0.00002  dbSNP: rs397516292

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036072	SCV000059724	uncertain significance	not specified	2012-04-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Arg668Cys v ariant in MYO7A has not been reported in the literature nor previously identifie d by our laboratory. Computational analyses (biochemical amino acid properties, conservation, SIFT, PolyPhen2) suggest that the Arg668Cys variant may impact the protein, though this information is not predictive enough to determine pathogen icity. If the Arg668Cys variant is found to be in trans (on separate copies of t he gene) with the Tyr333X variant, then the presence of the Arg668Cys variant in combination with a pathogenic variant in a patient with hearing loss increases the likelihood that the Arg668Cys variant is pathogenic. In summary, the clinica l significance of this variant cannot be determined with certainty; however base d upon the arguments described above, and if the Arg668Cys variant is shown to b e in trans, we would lean towards a more likely pathogenic role for this variant .
GeneDx	RCV000489211	SCV000577639	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue p.(R668H) has been reported as pathogenic in the published literature in association with nonsyndromic hearing loss (Sang et al., 2013); This variant is associated with the following publications: (PMID: 20146813, 16283880, 26969326)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000489211	SCV001397007	pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 668 of the MYO7A protein (p.Arg668Cys). This variant is present in population databases (rs397516292, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 26969326; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43168). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. This variant disrupts the p.Arg668 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26969326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001810407	SCV002060379	uncertain significance	Usher syndrome type 1	2021-11-03	criteria provided, single submitter	clinical testing	NM_000260.3(MYO7A):c.2002C>T(R668C) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R668C has been observed in cases with relevant disease (PMID: 26969326, 16283880, 20146813). Functional assessments of this variant are not available in the literature. R668C has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.2002C>T(R668C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000489211	SCV005436168	likely pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	MYO7A: PM2, PM3, PM5, PP3
Fulgent Genetics, Fulgent Genetics	RCV005007941	SCV005632221	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2024-03-20	criteria provided, single submitter	clinical testing