Submissions for variant NM_001277269.2(OTOG):c.7517-5_7518dup

dbSNP: rs1295062471

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221901	SCV000272264	uncertain significance	not specified	2015-11-10	criteria provided, single submitter	clinical testing	The c.7517-5_7518dup variant in OTOG has been previously reported in one individ ual with hearing loss; however, a variant affecting the remaining copy of OTOG w as not detected in this individual and an alternate genetic explanation for thei r disease was identified(LMM unpublished data). Data from large population studi es is insufficient to assess the frequency of this variant. This variant is a ta ndem duplication of 7 base pairs that encompass the 3' splice junction of intron 43 in the OTOG gene. However, it is not clear whether this will result in splic ing to occur at a novel 3' splice site downstream of the nascent splice site, wh ich would not impact the protein, or if splicing occurs at the nascent splice si te, which would result in a frameshift of the coding sequence and therefore, be deleterious to the protein. Computational tools predict that splicing would occu r at the novel 3' splice site and thus would not result in a frameshift of the c oding sequence; however, functional studies are needed to determine which of the se scenarios is correct. In summary, the clinical significance of the c.7517-5_7 518dup variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000593594	SCV000700763	uncertain significance	not provided	2017-05-05	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001507310	SCV001712077	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 18B	2021-03-18	criteria provided, single submitter	research	OTOG c.7517-5_7518dup is predicted to introduce a cryptic splice acceptor within the sequence of the in-tandem duplication in OTOG intron 43. The cryptic splice acceptor in OTOG intron 43 occurs upstream of the OTOG exon 44 canonical splice and is predicted to result in inclusion of the mutant exon with the 7bp duplication leading to a premature stop. Consequence of this in-tandem duplication would be splicing of OTOG exon 44 occurring at the cryptic splice acceptor and resulting in a 7bp insertion in the OTOG message and premature stop at codon 2510 of 2926.
GeneDx	RCV000593594	SCV001826139	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	Identified with a second OTOG variant, phase unknown, in a patient with moderate sporadic hearing loss in the published literature (Safka Brozkova et al., 2020); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32860223)
CeGaT Center for Human Genetics Tuebingen	RCV000593594	SCV002062968	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000593594	SCV002373689	likely benign	not provided	2023-10-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001507310	SCV003810710	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 18B	2021-11-17	criteria provided, single submitter	clinical testing