Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000215443 | SCV000271245 | likely pathogenic | Rare genetic deafness | 2022-06-30 | criteria provided, single submitter | clinical testing | The p.Arg947X variant in MYO6 has been reported in one individual with progressive hearing loss that onset in the early 20s (Oka 2020 PMID: 32143290) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 947, which is predicted to lead to a truncated or absent protein. Truncating or loss-of-function variants in the MYO6 gene have been associated with autosomal recessive hearing loss as well as autosomal dominant hearing loss. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg947X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2_P. |
| Illumina Laboratory Services, |
RCV003389245 | SCV004101315 | pathogenic | Autosomal recessive nonsyndromic hearing loss 37 | 2023-08-18 | criteria provided, single submitter | clinical testing | The MYO6 c.2839C>T (p.Arg947Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a homozygous state. Based on the available evidence, the c.2839C>T (p.Arg947Ter) variant is classified as pathogenic for nonsyndromic hearing loss. |
| Victorian Clinical Genetics Services, |
RCV004786566 | SCV005398016 | pathogenic | Autosomal dominant nonsyndromic hearing loss 22 | 2024-09-23 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness 22 with or without hypertrophic cardiomyopathy (MIM#606346) and deafness 37 (MIM#607821) (DECIPHER; PMID: 30582396). Dominant-negative has also been suggested as mechanisms of disease associated with missense variants in this gene (PMID: 30582396). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified once as likely pathogenic by a clinical diagnostic laboratory (ClinVar). This variant has also been reported in one Japanese family with autosomal dominant hearing loss and classified as likely pathogenic (PMID: 32143290). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |