ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs766564988
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Total submissions: 5
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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
Invitae 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.

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