ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27621663)

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1778 of the OTOF protein (p.Val1778Phe). This variant is present in population databases (rs111033330, gnomAD 0.5%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 27621663). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48258). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. 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.

Variant summary: OTOF c.5332G>T (p.Val1778Phe) results in a non-conservative amino acid change located in the C2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251478 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00023 vs 0.0011). However, the frequency of the variant in the Ashkenazi Jewish population suggests a high carrier frequency (0.0051; gnomad). c.5332G>T has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness including four siblings from a large Ashkenazi Jewish family (Fedick_2016) and a patient reported to be compound heterozygous for the variant (reported from Fedick_2016 as a personal communication with the author). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27621663, 20146813). ClinVar contains an entry for this variant (Variation ID: 48258). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The OTOF c.5332G>T (p.Val1778Phe) variant has been reported in one study in which it was found in a homozygous state in four siblings affected with an autosomal recessive form of nonsyndromic sensorineural hearing loss, and in a heterozygous state in both parents and four unaffected siblings (Fedick et al. 2016). The affected individuals exhibited a variable degree of hearing loss from mild to moderately severe. The p.Val1778Phe variant was found in 13 of 1021 Ashkenazi Jewish controls and determined to have a carrier frequency of 1.27%, suggesting a founder variant, and is reported at a frequency of 0.004827 in the Ashkenazi Jewish population of the Genome Aggregation Database. The valine residue at this position is in a highly conserved region (Fedick et al. 2016). A second variant has been reported in a heterozygous state in one Japanese individual affected with hearing loss, at the same nucleotide position (c.5332G>A) resulting in substitution of the valine residue with isoleucine (Iwasa et al. 2013). Based on the evidence, the p.Val1778Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The p.Val1778Phe variant (rs111033330) has been previously reported in association with auditory neuropathy in an Ashkenazi Jewish family (Fedick 2016). Fedick et al reported 4 siblings homozygous for the p.Val1778Phe variant with highly variable degrees of hearing loss (mild to moderately -severe) and auditory brainstem response testing consistent with auditory neuropathy/dys-synchrony. This variant has been reported to ClinVar (Variation ID: 48258) and according to information provided by Fedick et al the entry from Partners HealthCare represents a 2nd Jewish family with the p.Val1778Phe variant in trans with a known pathogenic variant, but that information is not available on ClinVar. The p.Val1778Phe variant is predicted to be more frequent in Ashkenazi Jewish individuals than in other populations with an estimated frequency of 0.4 - 1.27 percent (gnomAD, and Fedick 2016). Altogether, there is not enough evidence to classify the p.Val1778Phe variant with certainty.

NM_194248.2:c.5332G>T in the OTOF gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This c.5332G>T (p.Val1778Phe) variant has been reported in one study in which it was found in a homozygous state in four siblings affected with an autosomal recessive form of nonsyndromic sensorineural hearing loss, and in a heterozygous state in both parents and four unaffected siblings (PMID: 27621663). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PP3, PP4, PM3_Supporting.