ClinVar Genomic variation as it relates to human health

The c.6046+1G>A variant in MYO15A has been reported in the heterozygous state in one European individual with nonsyndromic sensorineural hearing loss (Schrauwe n, 2013). This variant has also been identified in 1/8431 European American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/ ; dbSNP rs201978571). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. The c.6046+1G>A variant occurs in the invariant region (+ 1/2) of the 5' s plice site consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria t o be classified as pathogenic for sensorineural hearing loss in an autosomal rec essive manner (http://pcpgmwww.partners.org/personalizedmedicince/LMM).

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 36555390, 29196752, 36401330, 23208854)

This variant was identified in an homozygous state in a male patient with severe bilateral hearing loss. Both parents are asymptomatic heterozygous carriers of the variant.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal recessive (MIM#600316). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported at least three individuals with hearing impairment, although in one of these individuals, the second variant remains unknown. It has also been classified as pathogenic by a diagnostic laboratory in ClinVar (PMID: 23208854, 29196752). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change affects a donor splice site in intron 27 of the MYO15A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs201978571, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with deafness (PMID: 23208854, 29196752). ClinVar contains an entry for this variant (Variation ID: 164536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.