Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV002235474 | SCV002512115 | likely pathogenic | Nonsyndromic genetic hearing loss | 2021-07-27 | reviewed by expert panel | curation | The c.9517+2T>C variant in MYO15A is within the canonical splice site (+/- 1,2) of exon 57/66 and is predicted to cause altered splicing in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). This variant has been detected in 1 proband with hearing loss with a second variant of uncertain significance in MYO15A where phase was not determined (PMID: 26969326). The c.9517+2T>C variant was present in 0.002898% (1/34,510) of Latino/Admixed American alleles in gnomAD v2, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, the c.9517+2T>C variant in MYO15A meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting. |
Laboratory for Molecular Medicine, |
RCV000825569 | SCV000966898 | pathogenic | Rare genetic deafness | 2018-03-05 | criteria provided, single submitter | clinical testing | The c.9517+2T>C variant in MYO15A has been reported in 1 individual with hearing loss, who also harbored a second likely pathogenic variant in MYO15A (Sloan-Heg gen 2016). It has been identified in 1/245472 chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org/), which is low enough to be consistent with a recessive carrier frequency. This variant occurs in the in variant region (+/- 1,2) of the splice consensus sequence and is predicted to ca use altered splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for hearing loss in an aut osomal recessive manner based upon predicted impact to the protein, low frequenc y in the general population, and presence in an affected individual. ACMG/AMP Cr iteria applied: PVS1, PM2, PM3. |
ARUP Laboratories, |
RCV001001764 | SCV001159383 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 3 | 2018-10-15 | criteria provided, single submitter | clinical testing | The c.9517+2T>C variant has been previously reported in a patient with non-syndromic hearing loss who also carried an additional pathogenic variant in MYO15A (Sloan-Heggen 2016). This variant affects the canonical splice donor sequence in intron 57, and is predicted to completely abrogate splicing at this junction (Alamut software v2.9). Consistent with an autosomal recessive carrier frequency, this variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.0004% (identified in 1 out of 245,472 chromosomes). Taken together, the c.9517+2T>C variant is likely to be pathogenic. |
Fulgent Genetics, |
RCV001001764 | SCV002791848 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 3 | 2021-09-07 | criteria provided, single submitter | clinical testing |