Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003313044 | SCV004012852 | likely pathogenic | Nonsyndromic genetic hearing loss | 2023-06-29 | reviewed by expert panel | curation | The c.5374C>T variant in OTOF is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1792. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16256 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). 1 different missense variant, c.5375G>A (p.R1792H) (PMID: 29048421, ClinVar Variation ID: 48259), in the same codon has been classified as likely pathogenic for nonsyndromic hearing loss by multiple submitters in ClinVar (PM5). This variant has been detected in at least 3 individuals with AR deafness. For two of those individuals, both were compound heterozygous for the variant and a VUS meeting PM2_Supporting, and both of those were confirmed in trans by family testing (c.2676G>A (p.K892K) which occurs at the last nucleotide in exon (22) of OTOF and c.4748G>A (p.R1583H), 1.5 PM3 points, PMID: 34416374, Universitätsmedizin Göttingen, Institute of Human Genetics/Institute of Auditory Neuroscience & InnerEarLab) (PM3). At least one patient was compound heterozygous for this variant and the p.K892K variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for autosomal recessive deafness (PP4, PMID: 34416374). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3, PM5 (ClinGen Hearing Loss VCEP specifications version 2; 6/27/2022). |
| Laboratory for Molecular Medicine, |
RCV000155251 | SCV000204937 | uncertain significance | not specified | 2016-09-15 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Invitae | RCV003114303 | SCV003786372 | likely pathogenic | not provided | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1792 of the OTOF protein (p.Arg1792Cys). This variant is present in population databases (rs142111099, gnomAD 0.007%). This missense change has been observed in individuals with OTOF-related conditions (PMID: 31095577, 34416374, 34536124; Invitae). ClinVar contains an entry for this variant (Variation ID: 178503). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTOF protein function with a positive predictive value of 80%. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been observed in individuals with OTOF-related conditions (PMID: 29048421), which suggests that this may be a clinically significant amino acid residue. 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. |