Submissions for variant NM_001292063.2(OTOG):c.499del (p.Val167fs)

dbSNP: rs876657657

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218007	SCV000271254	likely pathogenic	Rare genetic deafness	2016-02-04	criteria provided, single submitter	clinical testing	The p.Val179fs variant in OTOG has not been previously reported in individuals w ith hearing loss. This variant has been identified in 1/722 of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org); h owever, this frequency is low enough to be consistent with a recessive carrier f requency. This variant is predicted to cause a frameshift, which alters the prot ein?s amino acid sequence beginning at position 179 and leads to a premature ter mination codon 53 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schrader s 2012), and disruption of Otog in mice resulted in deafness supporting of a los s-of-function mechanism for the disease (Simmler 2000). While these two studies provide evidence of a causative link between loss of function of OTOG and autoso mal recessive hearing loss, to date, no other publications report on OTOG varian ts in individuals with hearing loss. In summary, although additional evidence is required to strengthen the gene-disease association for OTOG and hearing loss, the current data supports a likely pathogenic role for the p.Val179fs variant.
GeneDx	RCV000487342	SCV000573779	pathogenic	not provided	2025-02-07	criteria provided, single submitter	clinical testing	Identified with a second variant, phase unknown, in a patient with severe-profound bilateral sensorineural hearing loss in the published literature (PMID: 36515421); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 36147510, 36515421)
Athena Diagnostics	RCV000487342	SCV000842986	likely pathogenic	not provided	2018-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000487342	SCV004549320	pathogenic	not provided	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val179Trpfs*53) in the OTOG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs751127167, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 228284). For these reasons, this variant has been classified as Pathogenic.