Submissions for variant NM_001378609.3(OTOGL):c.236-2A>G

gnomAD frequency: 0.00009  dbSNP: rs766564988

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826009	SCV000967497	uncertain significance	not specified	2019-02-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.209-2A>G variant in OTOGL has not been previously reported in individuals with hearing loss but has been identified in 0.1% (10/9830) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing; however, it is unknown whether this variant would result in use of a cryptic splice site or skipping of exon 5. Furthermore, exon 5 is in-frame and it is unknown whether skipping of this exon would lead to an abnormal or absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.209-2A>G variant is uncertain. ACMG/AMP criteria applied: PVS1_Moderate, BS1_Supporting.
Revvity Omics, Revvity	RCV001784459	SCV002020203	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 84B	2022-06-29	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001784459	SCV002580877	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 84B	2022-06-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001784459	SCV002788533	uncertain significance	Autosomal recessive nonsyndromic hearing loss 84B	2022-01-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003574810	SCV004335627	likely pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the OTOGL 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 OTOGL are known to be pathogenic (PMID: 23122586). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 667305). 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.
GeneDx	RCV003574810	SCV005331772	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359596	SCV005920622	uncertain significance	Nonsyndromic genetic hearing loss	2021-09-11	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004751750	SCV005366699	uncertain significance	OTOGL-related disorder	2024-09-26	no assertion criteria provided	clinical testing	The OTOGL c.209-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be higher than expected for causative undocumented variant. Variants that disrupt the consensus splice acceptor site in OTOGL are expected to be pathogenic. However, predicted exon 5 skipping would lead to inframe deletion, rather than to protein truncation. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.