Submissions for variant NM_000260.4(MYO7A):c.3283G>A (p.Glu1095Lys)

gnomAD frequency: 0.00049  dbSNP: rs199810429

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220951	SCV000272152	uncertain significance	not specified	2015-08-17	criteria provided, single submitter	clinical testing	The p.Glu1095Lys variant in MYO7A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 0.08% (52/6523 0) European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs199810429). Although this variant has been seen in th e general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. This variant is located in the last three bases of the exon, which is part of the 5? splice region. Comput ational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical signi ficance of thep.Glu1095Lys variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000585568	SCV000339399	uncertain significance	not provided	2016-02-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000299195	SCV000374335	likely benign	Autosomal dominant nonsyndromic hearing loss 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000337813	SCV000374336	uncertain significance	Usher syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000390552	SCV000374337	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000585568	SCV000692722	uncertain significance	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000585568	SCV001416463	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1095 of the MYO7A protein (p.Glu1095Lys). This variant is present in population databases (rs199810429, gnomAD 0.08%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 30718709). ClinVar contains an entry for this variant (Variation ID: 229005). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375348	SCV001572066	uncertain significance	Pendred syndrome	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Supporting, PP3_Supporting
GeneDx	RCV000585568	SCV001776242	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Identified with a second MYO7A variant in a patient with retinitis pigmentosa in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Jespersgaard et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30718709)
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787855	SCV000926870	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001276699	SCV001463207	uncertain significance	Usher syndrome type 1B	2020-04-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585568	SCV001959920	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000585568	SCV001968815	likely benign	not provided		no assertion criteria provided	clinical testing