Submissions for variant NM_001292063.2(OTOG):c.7418del (p.Arg2473fs)

gnomAD frequency: 0.00007  dbSNP: rs751369871

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089570	SCV001244775	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 18B	2018-07-18	criteria provided, single submitter	clinical testing	A homozygous frameshift deletion variant, NM_001277269.1(OTOG):c.7454delG, has been identified in exon 43 of 55 of the OTOG gene. This deletion is predicted to create a frameshift starting at amino acid position 2485, introducing a stop codon 77 residues downstream (NP_001264198.1(OTOG):p.(Arg2485Hisfs*77)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. However, truncation of the protein as a result of a NMD-escape mechanism has not been excluded. The variant is present in the gnomAD database at a frequency of 0.02% (36 heterozygotes). This variant has not been previously reported in clinical cases. However, multiple variants resulting in a premature stop-codon upstream of this variant have been previously reported as pathogenic in individuals with autosomal recessive deafness (Yu, S. et al. (2018), Schraders, M. et al. (2012), ClinVar, HGMD). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
AiLife Diagnostics, AiLife Diagnostics	RCV002223266	SCV002501545	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV002223266	SCV004012399	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	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: 34148116, 31827275, 31152317)
Invitae	RCV002223266	SCV004535432	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 869476). This premature translational stop signal has been observed in individual(s) with sensorineural hearing loss (PMID: 31152317). This variant is present in population databases (rs751369871, gnomAD 0.1%). This sequence change creates a premature translational stop signal (p.Arg2485Hisfs*77) 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).
PreventionGenetics, part of Exact Sciences	RCV003945802	SCV004766504	likely pathogenic	OTOG-related condition	2023-10-27	criteria provided, single submitter	clinical testing	The OTOG c.7454delG variant is predicted to result in a frameshift and premature protein termination (p.Arg2485Hisfs*77). This variant was reported in the homozygous and compound heterozygous state along with a nonsense variant in two patients with sensorineural hearing loss (Table S1, van Beeck Calkoen. 2019. PubMed ID: 31152317; Downie. 2019. PubMed ID: 31827275; Bahena. 2021. PubMed ID: 34148116).This variant is reported in 0.14% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17655765-CG-C). Frameshift variants in OTOG are expected to be pathogenic. This variant is interpreted as likely pathogenic.