Submissions for variant NM_001378609.3(OTOGL):c.1585C>T (p.Gln529Ter)

gnomAD frequency: 0.00007  dbSNP: rs371465450

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598640	SCV000710001	pathogenic	not provided	2018-09-17	criteria provided, single submitter	clinical testing	The Q520X variant in the OTOGL gene has been reported previously in association with hearing impairment in an affected individual who was compound heterozygous for the Q520X variant and another nonsense variant (Bonnet et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q520X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q520X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000598640	SCV003441146	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	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 sequence change creates a premature translational stop signal (p.Gln520*) in the OTOGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). This premature translational stop signal has been observed in individual(s) with OTOGL-related conditions (PMID: 23850727). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 503724).
CeGaT Center for Human Genetics Tuebingen	RCV000598640	SCV004700115	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	OTOGL: PVS1, PM2
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000844972	SCV005685143	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 84B	2024-05-16	criteria provided, single submitter	clinical testing	The OTOGL c.1585C>T (p.Gln529Ter) variant has been reported as c.1558C>T (p.Gln520Ter) in a compound heterozygous state with a second nonsense variant in an individual with mild hearing loss (Bonnet C et al., PMID: 23850727). This variant is only observed on 7/141,578 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature stop, which is predicted to lead to nonsense mediated decay. This variant has been reported in the ClinVar database as a pathogenic variant by three submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000844972	SCV005920620	pathogenic	Autosomal recessive nonsyndromic hearing loss 84B	2023-09-22	criteria provided, single submitter	research
GenomeConnect, ClinGen	RCV000844972	SCV000986798	not provided	Autosomal recessive nonsyndromic hearing loss 84B		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported most recently on 06-29-2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.