Submissions for variant NM_000260.4(MYO7A):c.5648G>A (p.Arg1883Gln)

gnomAD frequency: 0.00004  dbSNP: rs111033215

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844722	SCV000059851	pathogenic	Rare genetic deafness	2018-06-26	criteria provided, single submitter	clinical testing	The p.Arg1883Gln variant in MYO7A has been reported in 4 individuals with Usher Syndrome Type I (USH1), all of whom also carried a second pathogenic variant (Ou yang 2005, Nakanishi 2010, Bonnet 2011, Le Quesne Stabej 2012, Jacobson 2011). T he p.Arg1883Gln variant has been identified in 0.0088% (3/34194) Latino chromoso mes and 0.004% (10/274046) of total chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033215). Although this variant has been seen in the general population, its overall frequency is low en ough to be consistent with a recessive carrier frequency. Computational predicti on tools and conservation analysis suggest that the p.Arg1883Gln variant may imp act the protein. In summary, this variant meets criteria to be classified as pat hogenic for autosomal recessive Usher syndrome based upon multiple occurrences a s a compound heterozygous variant with pathogenic variants in the same gene in i ndividuals with Usher syndrome, low frequency in the gnomAD database, and predic ted impact on protein. ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supportin g, PP3, PP4.
GeneDx	RCV000413954	SCV000490900	pathogenic	not provided	2018-06-22	criteria provided, single submitter	clinical testing	The R1883Q missense variant in the MYO7A gene has been reported previously in association with Usher syndrome type IB, and has been reported in trans with a pathogenic variant on the opposite allele (in trans) in multiple individuals (Ouyang et al., 2005; Nakanishi et al., 2010; Bonnet et al., 2011; Le Quesne Stabej et al., 2012). The R1883Q variant is observed in 3/34194 (0.009%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The R1883Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We classify this variant as pathogenic.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000036199	SCV000891609	likely pathogenic	Usher syndrome type 1	2017-12-30	criteria provided, single submitter	curation
Invitae	RCV000413954	SCV000964064	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1883 of the MYO7A protein (p.Arg1883Gln). This variant is present in population databases (rs111033215, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 20844544, 21569298, 21873662, 22135276). 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: 43294). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000413954	SCV001446991	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000983988	SCV000797165	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2018-01-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001273516	SCV001456627	pathogenic	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing
Refractive Surgery Department, Bright Eye Hospital	RCV000036199	SCV002508889	likely pathogenic	Usher syndrome type 1	2022-05-13	no assertion criteria provided	clinical testing	WES identified two novel compound heterozygous mutations (c.5648G>A(rs111033215) and c.6238-1G>C) in MYO7A in two patients with Usher syndrome type 1. We found that the mutation c.5648G>A was predicted as “Probably Damaging” by the PolyPhen2 analysis. It was also evaluated as “Deleterious” and “Disease Causing” by other prediction programs (SIFT, PROVEIN, MutationTaster). Thus, the mutation of c.5648G>A was potentially pathogenic.