Submissions for variant NM_004999.4(MYO6):c.3029G>A (p.Arg1010Gln)

gnomAD frequency: 0.00004  dbSNP: rs374966499

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001164578	SCV001326711	uncertain significance	Autosomal dominant nonsyndromic hearing loss 22	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	RCV001164579	SCV001326712	uncertain significance	Autosomal recessive nonsyndromic hearing loss 37	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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV001164578	SCV005397707	uncertain significance	Autosomal dominant nonsyndromic hearing loss 22	2024-05-29	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 3029 of the coding sequence of the MYO6 gene that results in an arginine to glutamine amino acid change at residue 1010 of the myosin VI protein. The 1010 residue falls in the motif interacting with ubiquitin domain (PMID: 26971995). This is a previously reported variant (ClinVar 911845) that has been observed in individuals affected by non-syndromic deafness (PMID: 23767834) or age-related hearing loss (PMID: 36788145). This variant is present in 45 of 1,1613,306 alleles (0.003%) in the gnomAD v4.1.0 population dataset. Multiple bioinformatic tools provide conflicting predictions concerning this amino acid change though the Arg1010 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV005093682	SCV005767490	uncertain significance	not provided	2024-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1010 of the MYO6 protein (p.Arg1010Gln). This variant is present in population databases (rs374966499, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MYO6-related conditions. ClinVar contains an entry for this variant (Variation ID: 911845). 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 MYO6 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.