Submissions for variant NM_194248.3(OTOF):c.2239G>T (p.Glu747Ter)

dbSNP: rs397515591

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211840	SCV000199794	pathogenic	Rare genetic deafness	2017-05-04	criteria provided, single submitter	clinical testing	The p.Glu747X variant in OTOF has been reported in the homozygous state in four individuals with hearing loss, including 1 individual with auditory neuropathy b ased on the presence of otoacoustic emissions (Rodriguez-Ballesteros 2008 and LM M data). This variant has been identified in 1/33574 Latino chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs39 7515591); however, this frequency is low enough to be consistent with a recessiv e carrier frequency for hearing loss. This nonsense variant leads to a prematur e termination codon at position 747, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive auditory neuropathy spectrum disorder, based on the predicted impact to the protein, reported homozygosity in multiple affected individuals with consistent specific phenotypes, and the low frequency in the g eneral population.
GeneDx	RCV000318963	SCV000329896	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26188103, 18381613, 27766948, 29048421, 34194829, 32747562)
King Laboratory, University of Washington	RCV000056026	SCV001976367	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2020-08-01	criteria provided, single submitter	research	OTOF c.2239G>T, p.E747* is homozygous in 2 children with profound pre-lingual hearing loss in a Palestinian family (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 1/249840 allele on gnomAD, as a heterozygote
Invitae	RCV000318963	SCV004292093	pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu747*) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs397515591, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with OTOF-related conditions (PMID: 18381613, 27766948). ClinVar contains an entry for this variant (Variation ID: 65787). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003905022	SCV004727419	pathogenic	OTOF-related condition	2024-02-06	criteria provided, single submitter	clinical testing	The OTOF c.2239G>T variant is predicted to result in premature protein termination (p.Glu747*). This variant has been reported as causative for autosomal recessive nonsyndromic hearing loss (Rodriguez-Ballesteros et al. 2008. PubMed ID: 18381613; Santarelli et al. 2015. PubMed ID: 26188103; Dallol et al. 2016. PubMed ID: 27766948; described as c.169G>T p.Glu57* in Almontashiri et al. 2018. PubMed ID: 29048421). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in OTOF are expected to be pathogenic. This variant is interpreted as pathogenic.
GeneReviews	RCV000056026	SCV000087086	not provided	Autosomal recessive nonsyndromic hearing loss 9		no assertion provided	literature only
OMIM	RCV000056026	SCV000804277	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2008-06-01	no assertion criteria provided	literature only