Submissions for variant NM_001292063.2(OTOG):c.7693+1G>A

gnomAD frequency: 0.00091  dbSNP: rs548496846

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727025	SCV000680945	uncertain significance	not provided	2024-04-03	criteria provided, single submitter	clinical testing	Observed without another OTOG variant in a patient with hearing loss in published literature (PMID: 29196752); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29196752)
Eurofins Ntd Llc (ga)	RCV000727025	SCV000705006	uncertain significance	not provided	2017-01-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000578688	SCV000711746	uncertain significance	not specified	2018-03-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.7729+1G>A variant in OTOG has been reported in the heterozygous state in one individual w ith hearing loss (Baux 2017) and has been identified by our laboratory in the he terozygous state in 2 individuals with hearing loss, both of whom had pathogenic variants in other genes sufficient to explain their hearing loss. This variant has also been identified in 0.2% (101/60880) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs5484 96846). Although this variant has been seen in the general population, its frequ ency is not high enough to rule out a pathogenic role. This variant occurs in th e invariant region (+/- 1,2) of the splice consensus sequence of exon 45; howeve r, exon 45 is in-frame and it is unclear if altered splicing will lead to an in- frame deletion of exon 45 or an absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.7729+1G>A va riant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate.
Fulgent Genetics, Fulgent Genetics	RCV000763724	SCV000894608	uncertain significance	Autosomal recessive nonsyndromic hearing loss 18B	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727025	SCV001245639	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	OTOG: PVS1:Moderate, BS1:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727025	SCV003260443	likely pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 45 of the OTOG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs548496846, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 29196752). ClinVar contains an entry for this variant (Variation ID: 488980). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Revvity Omics, Revvity	RCV000763724	SCV003816547	uncertain significance	Autosomal recessive nonsyndromic hearing loss 18B	2022-01-25	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000727025	SCV001954757	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727025	SCV001971765	pathogenic	not provided		no assertion criteria provided	clinical testing