ClinVar Miner

Submissions for variant NM_016239.4(MYO15A):c.5925G>A (p.Trp1975Ter) (rs375290498)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000216211 SCV000272108 uncertain significance not specified 2015-03-02 criteria provided, single submitter clinical testing The p.Trp1975X variant in MYO15A has been reported in one Iranian individual wit h nonsyndromic hearing loss and segregated with disease in 6 family members, all of whom were homozygous for the variant (Fattahi 2012). However, this variant h as also been identified in 1.7% (138/8086) of South Asian chromosomes including 2 individuals who were homozygous by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs375290498). In addition, this nonsense vari ant 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 f unctionally relevant. Although the segregation data reported in the Iranian fami ly above (Fattahi 2012) suggests pathogenicity for this variant, it is not uncom mon to detect homozygous variants in families with consanguinity and/or in isola ted ethnic groups as is the case with this family, and it is possible that anoth er variant on the same chromosome as this variant is causative for disease in th e family. In summary, due to conflicting data, the clinical significance of the p.Trp1975X variant is uncertain.
GeneDx RCV000255905 SCV000321916 pathogenic not provided 2016-01-25 criteria provided, single submitter clinical testing The W1975X pathogenic variant in the MYO15A gene has been reported previously in thehomozygous state in multiple individuals in a consanguineous Iranian family in association withhearing loss (Fattahi et al., 2012). This variant is predicted to cause loss of normal protein functioneither through protein truncation or nonsense-mediated mRNA decay. The 1000 Genomes Databasereports W1975X was observed in 24/978 (2.5%) alleles from individuals of South Asian backgroundwith no homozygous individuals reported. We interpret W1975X as a pathogenic variant.
Invitae RCV000255905 SCV001045519 benign not provided 2019-12-31 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
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185531 SCV000238406 pathogenic Deafness, autosomal recessive 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.

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