Submissions for variant NM_016239.4(MYO15A):c.1137del (p.Tyr380fs)

dbSNP: rs769260536

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV002232560	SCV002512114	likely pathogenic	Nonsyndromic genetic hearing loss	2021-09-28	reviewed by expert panel	curation	The c.1137del (p.Tyr380fsTer64) variant in MYO15A variant 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). The filtering allele frequency of this variant is 0.014% for non-Finnish European chromosomes in gnomAD (95% CI of 26/128476). The p.Tyr380fsTer64 and another likely pathogenic or pathogenic variant were identified in 3 individuals with hearing loss, but phasing wasn't determined (PMIDs: 28000701, 31827275, 23208854; PM3). Two additional case observations were not counted due to phenotypes inconsistent with MYO15A: a case with hearing loss and RP and a case with progressive hearing loss (PMIDs: 24123792, 24875298). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3.
Eurofins Ntd Llc (ga)	RCV000597925	SCV000705841	pathogenic	not provided	2017-02-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779205	SCV000915746	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2017-09-01	criteria provided, single submitter	clinical testing	The MYO15A c.1137delC (p.Tyr380MetfsTer64) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has been reported in a compound heterozygous state along with a second null variant in three individuals with hearing loss (Schrauwen et al. 2013; Neveling et al. 2013; Vona et al. 2014). The individual identified in the Vona et al. (2014) study also carried the c.7C>G (p.Gln3Glu) missense variant in the MYH9 gene. The p.Tyr380MetfsTer64 variant was absent from nine normal hearing controls, but is reported at a frequency of 0.00038 in the European American population of the Exome Sequencing Project. Based on the evidence and due to the potential impact of frameshift variants, the p.Tyr380MetfsTer64 is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000779205	SCV001244797	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2017-11-24	criteria provided, single submitter	clinical testing	A heterozygous frameshift deletion variant, NM_016239.3(MYO15A):c.1137delC, has been identified in exon 2 of 66 of the MYO15A gene. This deletion is predicted to create a frameshift starting at amino acid position 380, introducing a stop codon 64 residues downstream, NP_057323.3(MYO15A):p.(Tyr380Metfs*64). This variant is predicted to result in loss of protein function either through truncation (loss of majority of the protein, including all functional domains) or nonsense-mediated decay. The variant is present in the gnomAD database at a frequency of 0.01% (28 heterozygotes) andhas been previously described as a compound heterozygote with a second truncating variant in two patients with hearing loss (Schrauwen, I., et al. (2013), Vona, B. et al. (2014)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195292	SCV001365603	pathogenic	Rare genetic deafness	2020-04-02	criteria provided, single submitter	clinical testing	The p.Tyr380MetfsX64 variant in MYO15A has been previously reported in at least 3 individuals with hearing loss who were compound heterozygous for a second truncating MYO15A variant (Neveling 2013, Schrauwen 2013, Vona 2014, Zazo Seco 2017, Hou 2020). This variant has been identified in 0.02% (26/128476) of European chromosomes by gnomad chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 380 and leads to a premature termination codon 64 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYO15A gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375258	SCV001571736	pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Very strong, PS1_Strong, PM2_Supporting, PP1_Supporting
Invitae	RCV000597925	SCV003441730	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr380Metfs*64) 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 (rs769260536, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with MYO15A-related conditions (PMID: 23208854, 24123792). This variant is also known as c.1134delC. ClinVar contains an entry for this variant (Variation ID: 500061). For these reasons, this variant has been classified as Pathogenic.