Submissions for variant NM_017433.5(MYO3A):c.4681C>T (p.Arg1561Ter)

gnomAD frequency: 0.00020  dbSNP: rs138593211

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778282	SCV000914458	uncertain significance	Autosomal recessive nonsyndromic hearing loss 30	2017-04-27	criteria provided, single submitter	clinical testing	The MYO3A c.4681C>T (p.Arg1561Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg1561Ter variant has been reported in one individual with hearing loss who was part of a study evaluating response to cochlear implantation. This individual carried the p.Arg1561Ter variant in a heterozygous state and also carried a second missense variant, but it is not clear if this second variant was present in cis or trans relative to p.Arg1561Ter (Wu et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00114 in the African American population from the Exome Sequencing Project. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for recessively inherited nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000778282	SCV001251548	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 30		criteria provided, single submitter	research	The MYO3A c.4681C>T (p.R1561*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been reported in the compound heterozygous state in one individual with profound sensorineural hearing impairment (PMID: 26166082).
Johns Hopkins Genomics, Johns Hopkins University	RCV000778282	SCV001425370	uncertain significance	Autosomal recessive nonsyndromic hearing loss 30	2020-05-14	criteria provided, single submitter	clinical testing	This nonsense variant results in a premature stop codon within the last 50 base pairs of the penultimate exon of the gene, likely leading to a transcript that escapes nonsense-mediated decay and resulting in a truncated protein product. The function of the region predicted to be missing in the truncated protein is unclear at this time. MYO3A c.4681C>T has been previously reported in an individual with hearing loss, who also carried a missense variant in this gene. This MYO3A variant (rs138593211) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the East Asian subpopulation (gnomAD: 20/19954 alleles; 0.1%, no homozygotes). This patient's ethnicity is reported to be Pacific Islander. This variant has been reported in ClinVar. Due to insufficient evidence, we consider the clinical significance of c.4681C>T to be uncertain at this time.
GeneDx	RCV001564739	SCV001787948	uncertain significance	not provided	2021-12-03	criteria provided, single submitter	clinical testing	Observed in a patient with hearing loss in published literature (Wu et al., 2015); Nonsense variant predicted to result in protein truncation, although pathogenic loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 26166082)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001564739	SCV003296718	pathogenic	not provided	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1561*) in the MYO3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO3A are known to be pathogenic (PMID: 12032315, 23990876). This variant is present in population databases (rs138593211, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 26166082). ClinVar contains an entry for this variant (Variation ID: 631635). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000778282	SCV003817824	uncertain significance	Autosomal recessive nonsyndromic hearing loss 30	2019-06-04	criteria provided, single submitter	clinical testing