Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000373305 | SCV005726112 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 3 | 2024-11-20 | criteria provided, single submitter | clinical testing | Variant summary: MYO15A c.6863C>T (p.Ser2288Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-06 in 234646 control chromosomes. c.6863C>T has been reported in the literature in compound heterozygous individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss, including at least one case where it was reported in trans with a pathogenic variant (e.g. Wang_2021, Wonkam_2022, Wu_2022, Chen_2022, Zeng_2022, Pan_2022) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34974475, 34744965, 35440622, 35982127, 36568381, 35640668). ClinVar contains an entry for this variant (Variation ID: 322158). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ce |
RCV003238755 | SCV005437047 | likely pathogenic | not provided | 2024-11-01 | criteria provided, single submitter | clinical testing | MYO15A: PM2, PM3, PM5 |
| Gene |
RCV003238755 | SCV003936539 | likely pathogenic | not provided | 2023-11-03 | criteria provided, single submitter | clinical testing | Identified with a second MYO15A variant (phase unknown) in patients with childhood-onset bilateral sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 35440622); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34974475, 35440622) |
| Laboratory for Molecular Medicine, |
RCV000604391 | SCV000712122 | likely pathogenic | Rare genetic deafness | 2024-02-05 | criteria provided, single submitter | clinical testing | The p.Ser2288Leu variant in MYO15A has been identified in the compound heterozygous state in at least 8 individuals with hearing loss (Wonkam 2022 PMID: 35440622, Chen 2022 PMID: 34974475, Wu 2022 PMID: 35982127, LMM internal data), 5 of whom had a second disease causing variant in the MYO15A gene, including 4 confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 322158) and has been identified in 0.005% (1/18344) East Asian chromosomes, 0.004% (1/22666) African chromosomes, and 0.004% (3/74792) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org/, v.4.0.0). This low frequency is consistent with the carrier frequency for recessive hearing loss. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS4_Supporting. |
| Illumina Laboratory Services, |
RCV000373305 | SCV000401173 | pathogenic | Autosomal recessive nonsyndromic hearing loss 3 | 2025-02-13 | criteria provided, single submitter | clinical testing |