Submissions for variant NM_144672.4(OTOA):c.1172C>T (p.Ser391Leu)

dbSNP: rs727504599

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155779	SCV000205490	uncertain significance	not specified	2013-05-22	criteria provided, single submitter	clinical testing	The Ser391Leu variant in the OTOA gene has not been reported in individuals with hearing loss or in large population studies. Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest t hat the Ser391Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, additional informatio n is needed to fully assess the clinical significance of the Ser391Leu variant.
GeneDx	RCV001657889	SCV001874818	uncertain significance	not provided	2021-08-26	criteria provided, single submitter	clinical testing	Reported as a variant identified in a cohort of patients with congenital hearing loss; proband-specific clinical and variant information not provided; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34335733)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001657889	SCV002111244	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 391 of the OTOA protein (p.Ser391Leu). This variant is present in population databases (rs727504599, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of OTOA-related conditions (PMID: 36633841; internal data). ClinVar contains an entry for this variant (Variation ID: 179001). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV002466450	SCV002762668	uncertain significance	Autosomal recessive nonsyndromic hearing loss 22	2022-12-13	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV002466450	SCV003844159	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 22	2023-02-28	criteria provided, single submitter	research	This variant occurred in compound heterozygosity with an OTOA frameshift variant in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient’s family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as a variant of unknown significance and is found in 5 heterozygotes on gnomAD. Based on consistently predicted functional effect, compound heterozygosity with a loss-of-function variant, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003895060	SCV004709530	uncertain significance	OTOA-related disorder	2023-11-28	no assertion criteria provided	clinical testing	The OTOA c.1172C>T variant is predicted to result in the amino acid substitution p.Ser391Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. This variant has been reported in the hemizygous state along with a full gene deletion in one other patient undergoing genetic testing for hearing loss at PreventionGenetics. 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.