Submissions for variant NM_004999.4(MYO6):c.3176G>C (p.Arg1059Thr)

gnomAD frequency: 0.00020  dbSNP: rs202214380

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038302	SCV000061971	uncertain significance	not specified	2017-01-26	criteria provided, single submitter	clinical testing	The p.Arg1059Thr variant in MYO6 has now been identified by our laboratory in fo ur individuals with hearing loss; however, it was not clear whether the variant was responsible for the hearing loss due to the absence of a second MYO6 variant or a reported dominant family history. This variant has been identified in 0.03 % (21/66526) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202214380). Although this variant has be en seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact on the protein. This variant is located in the 5' splice consensus sequence. Computational tools suggest a po ssible impact to splicing, though this information is not predictive enough to d etermine pathogenicity. In summary, the clinical significance of the p.Arg1059Th r variant is uncertain.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626874	SCV000747577	uncertain significance	Male infertility; Infertility disorder	2017-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001159663	SCV001321389	likely benign	Autosomal dominant nonsyndromic hearing loss 22	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001159664	SCV001321390	uncertain significance	Autosomal recessive nonsyndromic hearing loss 37	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375277	SCV001571803	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Supporting
Invitae	RCV001723619	SCV002311817	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1059 of the MYO6 protein (p.Arg1059Thr). This variant also falls at the last nucleotide of exon 30, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202214380, gnomAD 0.04%). 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: 45153). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723619	SCV001953740	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723619	SCV001970146	uncertain significance	not provided		no assertion criteria provided	clinical testing