Submissions for variant NM_016239.4(MYO15A):c.3385C>T (p.Arg1129Ter)

gnomAD frequency: 0.00002  dbSNP: rs748868741

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607201	SCV000713219	pathogenic	Rare genetic deafness	2019-09-04	criteria provided, single submitter	clinical testing	The p.Arg1129X variant in MYO15A has been previously reported in at least 2 individuals with hearing loss (Sommen 2016, LMM unpublished data). One individual had a second likely pathogenic MYO15A variant identified, though phasing was not performed (LMM unpublished data). This variant has been identified in 0.04% (14/34518) of Latino chromosomes bygnomAD (http://gnomad.broadinstitute.org); however, its frequency is low enough to be consistent with a carrier frequency for hearing loss. This nonsense variant leads to a premature termination codon at position 1129, which is predicted to lead to a truncated or absent protein. Loss of MYO15A gene function 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_Supporting.
GeneDx	RCV001541806	SCV001759839	pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	Identified with a second variant in a patient with suspected autosomal recessive sensorineural hearing loss in published literature (PMID: 27068579); Nonsense 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: 34426522, 31589614, 34515852, 27068579)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001541806	SCV002232340	pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1129*) 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 (rs748868741, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 505802). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001824841	SCV002808881	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2021-10-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001824841	SCV003810568	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2022-06-22	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001541806	SCV001953487	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001541806	SCV001965928	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824841	SCV002075080	not provided	Autosomal recessive nonsyndromic hearing loss 3		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 03-02-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.