Submissions for variant NM_000260.4(MYO7A):c.2527G>A (p.Val843Met)

gnomAD frequency: 0.00024  dbSNP: rs140559111

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171529	SCV001334314	uncertain significance	Usher syndrome	2022-08-03	reviewed by expert panel	curation	The c.2527G>A variant in MYO7A is a missense variant predicted to cause substitution of valine by methionine at amino acid 843. The variant is present in 0.0006965 (23/22568) of South Asian alleles with a confidence interval of 95% in gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.25, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. The variant has been reported in 6 probands, all of whom did not have clinical/phenotypic data, had other potentially pathogenic variants, or did not present with hearing loss (PMID:30755392, GeneDx, EGL Eurofins, Illumina). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the absence of ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036089	SCV000059741	uncertain significance	not specified	2017-10-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val843Met var iant in MYO7A has been previously identified by our laboratory in one Caucasian individual with hearing loss. It has also been identified in 0.1% (23/22644) of South Asian chromosomes and in 72/163744 of the total chromosomes with the highe st frequency of 0.1% (23/22644) in South Asian chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140559111). Com putational prediction tools and conservation analysis suggest that the p.Val843M et variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val843Met variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015 ).
Illumina Laboratory Services, Illumina	RCV000367440	SCV000374302	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.
Illumina Laboratory Services, Illumina	RCV000274914	SCV000374303	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	RCV000318308	SCV000374304	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.
Eurofins Ntd Llc (ga)	RCV000658008	SCV000702277	uncertain significance	not provided	2016-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000658008	SCV000779779	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	Identified in one patient with multiple congenital anomalies and no reported hearing loss who also harbored variants in several other genes from a large cohort of patients who underwent WES (PMID: 30755392); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30755392)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658008	SCV001418150	benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000274914	SCV001805887	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000367440	SCV001805888	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000318308	SCV001805889	uncertain significance	Usher syndrome type 1	2021-07-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490493	SCV002778602	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2022-02-07	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000658008	SCV001921212	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658008	SCV001967103	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001835641	SCV002086628	uncertain significance	Usher syndrome type 1B	2020-01-27	no assertion criteria provided	clinical testing