Submissions for variant NM_016239.4(MYO15A):c.5925G>A (p.Trp1975Ter)

gnomAD frequency: 0.00005  dbSNP: rs375290498

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017472	SCV000272108	uncertain significance	Rare genetic deafness	2022-06-30	criteria provided, single submitter	clinical testing	The p.Trp1975X variant in MYO15A has been reported in one Iranian individual with nonsyndromic hearing loss and segregated with disease in 6 family members, all of whom were homozygous for the variant (Fattahi 2012). However, this variant has also been identified in 1.7% (138/8086) of South Asian chromosomes including 2 individuals who were homozygous by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375290498). In addition, this nonsense variant introduces a premature codon at position 1975 in exon 26 of the MYO15A; exon 26 is missing in some alternatively spliced transcripts of MYO15A identified in the inner ear (Liang 1999), raising the possibility that this exon may not be functionally relevant. Although the segregation data reported in the Iranian family above (Fattahi 2012) suggests pathogenicity for this variant, it is not uncommon to detect homozygous variants in families with consanguinity and/or in isolated ethnic groups as is the case with this family, and it is possible that another variant on the same chromosome as this variant is causative for disease in the family. In summary, due to conflicting data, the clinical significance of the p.Trp1975X variant is uncertain.. ACMG/AMP Criteria applied: BA1.
GeneDx	RCV000255905	SCV000321916	benign	not provided	2020-12-23	criteria provided, single submitter	clinical testing	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: 29907799, 22736430, 10552926, 27375115, 26969326, 30096381, 31130284)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255905	SCV001045519	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000255905	SCV001251749	pathogenic	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000255905	SCV001880560	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000185531	SCV004237857	likely benign	Autosomal recessive nonsyndromic hearing loss 3	2023-11-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255905	SCV004698212	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MYO15A: BS1
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185531	SCV000238406	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2014-06-23	no assertion criteria provided	research	The variant (c. 5925G>A;p.W1975*) is a nonsense variant, which is predicted to result in a truncated protein and considered pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255905	SCV001956120	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255905	SCV001963804	pathogenic	not provided		no assertion criteria provided	clinical testing