Submissions for variant NM_000260.4(MYO7A):c.4739A>G (p.Tyr1580Cys)

gnomAD frequency: 0.00018  dbSNP: rs370232066

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036161	SCV000059813	uncertain significance	not specified	2010-09-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Tyr1580Cys vari ant in MYO7A has not been reported in the literature nor previously identified b y our laboratory. The Tyrosine (Tyr) residue at position 1580 is conserved acros s mammals and some lower species and computational analyses (PolyPhen, SIFT, Ali gnGVGD) suggest that the Tyr1580Cys variant may impact the protein. However, thi s information is not predictive enough to assume pathogenicity. It should be not ed that this lab has only sequenced the MYO7A in approximately 200 individuals s uch that the full spectrum of benign variation has not yet been defined for this gene, increasing the possibility that this could be a benign variant. In summar y, the clinical significance of this variant cannot be determined with certainty at this time.
Illumina Laboratory Services, Illumina	RCV001109030	SCV001266335	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2018-01-12	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	RCV001114663	SCV001272565	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2018-01-12	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	RCV001114664	SCV001272566	uncertain significance	Usher syndrome type 1	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001246336	SCV001419682	uncertain significance	not provided	2024-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1580 of the MYO7A protein (p.Tyr1580Cys). This variant is present in population databases (rs370232066, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43256). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. 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	RCV001375116	SCV001572029	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM5_Moderate, PP3_Supporting
GeneDx	RCV001246336	SCV001795383	uncertain significance	not provided	2025-01-06	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a patient with hearing loss in published literature (PMID: 34753855); 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: 31260034, 34753855)
Natera, Inc.	RCV001271766	SCV001453192	uncertain significance	Usher syndrome type 1B	2020-04-17	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001246336	SCV001921041	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001246336	SCV001954803	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001246336	SCV001965176	uncertain significance	not provided		no assertion criteria provided	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814945	SCV005071148	uncertain significance	Retinal dystrophy	2021-01-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734545	SCV005357427	uncertain significance	MYO7A-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The MYO7A c.4739A>G variant is predicted to result in the amino acid substitution p.Tyr1580Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.