Submissions for variant NM_016239.4(MYO15A):c.3524dup (p.Ser1176fs)

gnomAD frequency: 0.00006  dbSNP: rs766187994

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000989770	SCV001140323	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2019-05-28	criteria provided, single submitter	clinical testing
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	RCV000989770	SCV001792220	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	research	in compound heterozygosis with the c.1615C>T variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic)
GeneDx	RCV001732007	SCV001981919	pathogenic	not provided	2024-07-19	criteria provided, single submitter	clinical testing	Identified in a patient with autosomal recessive sensorineural hearing loss who harbored a second MYO15A variant (phase unknown) in published literature (PMID: 30953472); Identified in 9/44 members of a Taiwanese cohort with autosomal recessive sensorineural hearing loss in published literature (PMID: 31581539) but additional evidence is not available; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35346193, 31581539, 34325055, 34416374, 34599368, 34943631, 35939872, 26810297, 34974475, 35982127, 38297847, 30953472)
Molecular Diagnosis Center for Deafness	RCV000989770	SCV001984891	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
3billion	RCV000989770	SCV002573120	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000803332 / PMID: 26810297). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000989770	SCV004222854	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: MYO15A c.3524dupA (p.Ser1176ValfsX14) results in a premature termination codon, 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 allele was found at a frequency of 0.00014 in 246816 control chromosomes. c.3524dupA has been reported in the literature inmultiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 3 (e.g., Fu_2022). These data indicate that the variant are likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 35939872). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001732007	SCV004298135	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1176Valfs*14) 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 (rs766187994, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with early onset deafness (PMID: 26810297, 30953472, 31581539, 34416374, 34599368, 34974475, 35346193). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3525_3526insA, p.Q1175fsX1188. ClinVar contains an entry for this variant (Variation ID: 803332). For these reasons, this variant has been classified as Pathogenic.