Submissions for variant NM_000260.4(MYO7A):c.5617C>T (p.Arg1873Trp)

gnomAD frequency: 0.00001  dbSNP: rs397516321

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036196	SCV000059848	pathogenic	Rare genetic deafness	2011-03-09	criteria provided, single submitter	clinical testing	The Arg1873Trp variant in MYO7A has been reported in five probands with Usher sy ndrome type 1 and has not been identified in 1176 control chromosomes (Roux 2006 , Baux 2008-unpublished data). All of these probands were homozygous or compound heterozygous. In summary, this variant meets our criteria to be classified as p athogenic.
Counsyl	RCV000668897	SCV000793571	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2017-08-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069199	SCV001234352	pathogenic	not provided	2024-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1873 of the MYO7A protein (p.Arg1873Trp). This variant is present in population databases (rs397516321, gnomAD 0.01%). This missense change has been observed in individuals with Usher syndrome (PMID: 16679490, 25558175, 27460420, 29142287). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43291). 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	RCV001069199	SCV001765992	pathogenic	not provided	2019-04-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28944237, 28472130, 27460420, 25558175, 16679490, 18484607, 21738395)
Athena Diagnostics	RCV001069199	SCV001879386	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323370	SCV004030130	pathogenic	Usher syndrome	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.5617C>T (p.Arg1873Trp) results in a non-conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense change (p.Arg1873Gln) has been classified as pathogenic (ClinVar). 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 247820 control chromosomes (gnomAD). c.5617C>T has been reported in the literature in multiple individuals affected with Usher Syndrome (Bahena_2022, Bonnet_2016, Mansard_2021), and some were reported as compound heterozygous with (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34948090, 34148116, 27460420). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003428	SCV005629476	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2024-02-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826553	SCV002088513	pathogenic	Usher syndrome type 1B	2021-03-02	no assertion criteria provided	clinical testing