Submissions for variant NM_017433.5(MYO3A):c.2275A>T (p.Asn759Tyr)

gnomAD frequency: 0.00030  dbSNP: rs201033926

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151460	SCV000199497	uncertain significance	not specified	2014-09-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Asn759Tyr var iant in MYO3A has been identified in three individuals with hearing loss, but no ne of them carries a second variant in the MYO3A gene (LMM unpublished data). Th is variant has also been identified in 0.06% (5/8600) of European American chrom osomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs201033926). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. The asparagi ne (Asn) at position 759 is moderately conserved in mammals and evolutionary dis tant species; however, several species of birds and reptiles carry a tyrosine (T yr) at this position, supporting that this change may be tolerated. Additional c omputational prediction tools suggest this variant may not impact the protein. I n summary, while the clinical significance of the p.Asn759Tyr variant is uncerta in, these data suggest that it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV000477832	SCV000361940	uncertain significance	Autosomal recessive nonsyndromic hearing loss 30	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.
GeneDx	RCV000657156	SCV000618370	uncertain significance	not provided	2024-04-09	criteria provided, single submitter	clinical testing	Identified in a patient with bilateral sensorineural hearing loss who also harbored several other variants in different genes in published literature (PMID: 29907799); 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: 29907799)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657156	SCV002188080	uncertain significance	not provided	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 759 of the MYO3A protein (p.Asn759Tyr). This variant is present in population databases (rs201033926, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MYO3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 164620). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO3A protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000477832	SCV002814343	uncertain significance	Autosomal recessive nonsyndromic hearing loss 30	2021-07-19	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477832	SCV000536798	uncertain significance	Autosomal recessive nonsyndromic hearing loss 30	2016-02-09	no assertion criteria provided	research