Submissions for variant NM_000260.4(MYO7A):c.721C>T (p.Arg241Cys)

dbSNP: rs782166819

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666535	SCV000790841	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2017-04-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380427	SCV001578497	pathogenic	not provided	2024-06-25	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 241 of the MYO7A protein (p.Arg241Cys). This variant is present in population databases (rs782166819, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive Usher syndrome or non-syndromic deafness (PMID: 10930322, 23770805, 26309859, 26338283). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438180). 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.
GeneDx	RCV001380427	SCV001813821	pathogenic	not provided	2021-03-24	criteria provided, single submitter	clinical testing	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: 28041643, 32581362, 26338283, 23770805, 26309859, 10930322, 33111992, 29625443)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505169	SCV004803776	pathogenic	Usher syndrome	2024-01-26	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.721C>T (p.Arg241Cys) 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 allele was found at a frequency of 1.2e-05 in 248472 control chromosomes. c.721C>T has been reported in the literature in multiple individuals affected with Usher Syndrome, autosomal recessive, including as a homozygous genotype (e.g. Shahzad_2013). 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. A different variant located at the same codon c.722G>A (p.Arg241His) has been classified as pathogenic by our lab supporting a critical relevance of this residue to MYO7A protein function. The following publication has been ascertained in the context of this evaluation (PMID: 23770805). ClinVar contains an entry for this variant (Variation ID: 438180). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005004198	SCV005632197	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2024-01-27	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505169	SCV000599126	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV001542592	SCV001760283	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001829440	SCV002093131	pathogenic	Usher syndrome type 1B	2020-06-19	no assertion criteria provided	clinical testing