Submissions for variant NM_016239.4(MYO15A):c.4777G>A (p.Glu1593Lys)

gnomAD frequency: 0.00008  dbSNP: rs376469502

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156731	SCV000206452	uncertain significance	not specified	2014-10-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1593Ly s variant in MYO15A has been identified by our laboratory in trans with another variant of uncertain significance in MYO15A in two individuals with hearing loss in one family. It has been identified in 0.01% (1/8420) of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs376469502). Although this variant has been seen in the general pop ulation, its frequency is not high enough to rule out a pathogenic role. Computa tional prediction tools and conservation analyses suggest that the Glu1593Lys va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, while available data suggest that it is more likely to be pathogenic, the clinical significance of this variant is uncer tain.
GeneDx	RCV001550103	SCV001770383	likely pathogenic	not provided	2024-11-22	criteria provided, single submitter	clinical testing	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: 27375115, 26969326, 32658404, 27344577, 35346193, 29196752, 32860223, 32617096, 32802042)
Molecular Diagnosis Center for Deafness	RCV002224962	SCV001984908	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001550103	SCV002219729	pathogenic	not provided	2024-06-21	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 1593 of the MYO15A protein (p.Glu1593Lys). This variant is present in population databases (rs376469502, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 26969326, 32860223; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 179930). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002224962	SCV002767401	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal recessive (MIM#600316). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 18 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin motor domain (NCBI, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five individuals with hearing impairment as both compound heterozygous or homozygous. While it has been classified as a VUS by a diagnostic laboratory in ClinVar, they also reported that the two affecteds in the family are compound heterozygous (PMID: 27344577, 29196752, 26969326). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV001550103	SCV004225754	likely pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	PP3, PM2_supporting, PM3_strong
Fulgent Genetics, Fulgent Genetics	RCV002224962	SCV005645967	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2024-02-23	criteria provided, single submitter	clinical testing