Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003120877 | SCV003799179 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 9 | 2022-07-21 | reviewed by expert panel | curation | The c.2215-1G>C variant in OTOF occurs within the canonical splice acceptor site (-1) of intron 18. It is predicted to cause skipping of biologically-relevant-exon 19 of 47, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic deafness based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PVS1 and PM2_P (ClinGen Hearing Loss VCEP specifications version 2; 7/21/2022). |
Invitae | RCV003560921 | SCV004292094 | pathogenic | not provided | 2023-02-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with congenital auditory neuropathy spectrum disorder (PMID: 26818607). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 18 of the OTOF 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 OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). |
Deafness Molecular Diagnostic Center, |
RCV003120877 | SCV002568102 | pathogenic | Autosomal recessive nonsyndromic hearing loss 9 | no assertion criteria provided | clinical testing |