Submissions for variant NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)

dbSNP: rs876657655

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001449942	SCV001334312	likely pathogenic	Usher syndrome type 1	2023-01-18	reviewed by expert panel	curation	The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID: 21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022). 1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223094	SCV000271250	likely pathogenic	Rare genetic deafness	2015-11-05	criteria provided, single submitter	clinical testing	The p.Lys2021Arg variant in MYO7A has been reported in one individual with type I Usher syndrome who was compound heterozygous for a second likely pathogenic va riant in MYO7A (Roux 2011). This variant was absent from large population studie s. Computational prediction tools and conservation analyses suggest that the p.L ys2021Arg variant may impact the protein. In summary, although additional studie s are required to fully establish its clinical significance, this variant is lik ely pathogenic based on the previous report in an individual with Usher syndrome .
Counsyl	RCV000675133	SCV000800711	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001449942	SCV001653419	likely pathogenic	Usher syndrome type 1	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV003126609	SCV003803420	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 21436283)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001449942	SCV004805076	likely pathogenic	Usher syndrome type 1	2024-03-17	criteria provided, single submitter	research
Natera, Inc.	RCV001275529	SCV001460744	likely pathogenic	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing