Submissions for variant NM_016239.4(MYO15A):c.10419_10423del (p.Ser3474fs)

dbSNP: rs2142436425

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnosis Center for Deafness	RCV001823229	SCV001984956	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001823229	SCV004021136	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: MYO15A c.10419_10423delCAGCT (p.Ser3474ProfsX42) located upstream of the nonsense mediated decay (NMD) region in the penultimate exon 65 results in a premature termination codon in the NMD region and predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 247850 control chromosomes. c.10419_10423delCAGCT has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with features of profound Autosomal Recessive Nonsyndromic Hearing Loss 3 (example, Liang_2021, Wang_2021, Wu_2022, Fu_2022). These data indicate that the variant is very 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: 35346193, 34265623, 33597575, 35982127). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003660896	SCV004376080	pathogenic	not provided	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser3474Profs*42) in the MYO15A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the MYO15A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 33597575, 34265623, 35346193). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1185620). For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001823229	SCV005416703	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_VeryStrong
Deafness Molecular Diagnostic Center, Chinese PLA General Hospital	RCV001823229	SCV001763605	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		no assertion criteria provided	case-control