Submissions for variant NM_000260.4(MYO7A):c.1007G>A (p.Arg336His)

gnomAD frequency: 0.00164  dbSNP: rs45629132

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001775058	SCV000840517	likely benign	Usher syndrome	2020-11-02	reviewed by expert panel	curation	The c.1007G>A (p.Arg336His) variant in MYO7A was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID: 16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036038	SCV000059690	likely benign	not specified	2015-08-11	criteria provided, single submitter	clinical testing	p.Arg336His in exon 10 of MYO7A: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (125/66438) of European chrom osomes including 1 homozygous individual by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs45629132). This variant has been re ported in the literature; however, there is no evidence to support pathogenicity . It was identified in a family with autosomal dominant hearing loss but found n ot to segregate with disease and therefore assumed to be benign (Luijendijk 2004 ). It was also identified in the heterozygous state in a proband with Usher synd rome without a second variant (Jaijo 2006).
Eurofins Ntd Llc (ga)	RCV000036038	SCV000339775	likely benign	not specified	2016-03-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765013	SCV000896197	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001034270	SCV001197607	likely benign	not provided	2024-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109645	SCV001267006	likely benign	Autosomal dominant nonsyndromic hearing loss 11	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001109646	SCV001267007	likely benign	Autosomal recessive nonsyndromic hearing loss 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001109647	SCV001267008	likely benign	Usher syndrome type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001109645	SCV001368190	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2019-09-24	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3.
Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)	RCV001526682	SCV001451439	uncertain significance	Meniere disease	2020-12-14	criteria provided, single submitter	case-control
GeneDx	RCV001034270	SCV001812977	likely benign	not provided	2020-08-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30311386, 30245029, 15221449, 16470552, 25262649)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001034270	SCV002009319	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001109647	SCV002060067	uncertain significance	Usher syndrome type 1	2021-11-04	criteria provided, single submitter	clinical testing	NM_000260.3(MYO7A):c.1007G>A(R336H) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R336H has been observed in cases with relevant disease (PMID: 23804846, 16470552, 33363762). Functional assessments of this variant are not available in the literature. R336H has been observed in population frequency databases (gnomAD: NFE 0.22%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.1007G>A(R336H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
PreventionGenetics, part of Exact Sciences	RCV003924905	SCV004744720	likely benign	MYO7A-related condition	2022-11-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001274696	SCV001459064	likely benign	Usher syndrome type 1B	2020-04-16	no assertion criteria provided	clinical testing