Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002232717 | SCV002512116 | pathogenic | Nonsyndromic genetic hearing loss | 2024-07-23 | reviewed by expert panel | curation | The allele frequency of the c.996C>G (p.Tyr332Ter) variant in the MYO15A gene is 0.004% (50/1179998) of European non-Finnish alleles by gnomAD v4.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The p.Tyr332Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 2/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). One proband with SNHL with a loss of function pathogenic variant but without parent testing was found in LMM internal data (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PVS1, PM3_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 7/23/2024) |
| Laboratory for Molecular Medicine, |
RCV000603268 | SCV000712319 | pathogenic | Rare genetic deafness | 2016-06-30 | criteria provided, single submitter | clinical testing | The p.Tyr332X variant in MYO15A has not been previously reported in individuals with hearing loss. It has been identified in 1/65810 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with the carrier frequency for recessive hearing loss. Thi s nonsense variant leads to a premature termination codon at position 332 which is predicted to lead to a truncated or absent protein. Loss of function of the M YO15A gene is an established disease mechanism in autosomal recessive nonsyndrom ic hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for nonsyndromic hearing loss in an autosomal recessive manner based on the predicted impact of the variant and extremely low allele frequency in th e general population. |
| Fulgent Genetics, |
RCV000762982 | SCV000893427 | pathogenic | Autosomal recessive nonsyndromic hearing loss 3 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001860245 | SCV002210047 | pathogenic | not provided | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr332*) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs759523751, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 505185). For these reasons, this variant has been classified as Pathogenic. |