Submissions for variant NM_194248.3(OTOF):c.4023+1G>A

gnomAD frequency: 0.00031  dbSNP: rs186810296

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041538	SCV000065233	uncertain significance	not specified	2021-04-07	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000897451	SCV001041596	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490336	SCV001302002	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000897451	SCV001825083	likely benign	not provided	2019-11-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33095980, 31130284, 31980526, 31581539, 30096381, 30245029, 26818607, 25262649, 26434960, 21935370, 31095577)
PreventionGenetics, part of Exact Sciences	RCV003390731	SCV004119907	uncertain significance	OTOF-related condition	2024-03-01	criteria provided, single submitter	clinical testing	The OTOF c.4023+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in a patient with auditory neuropathy spectrum disorder (ANSD) in the heterozygous state without a second potentially causative variant, and was reported in a second ANSD patient along with a variant of uncertain significance (Wang. 2011. PubMed ID: 21935370; Xiang. 2020. PubMed ID: 33095980). This variant is reported in 1.2% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-26693460-C-T), which is higher than expected for a disease causing variant in this gene. In two studies of hearing loss associated variants by expert groups this variant has been reported as benign (described as c.1953+1G>A in Table S4, Shearer. 2014. PubMed ID: 25262649; described as c.1722+1G>A in Table S3, Azaiez. 2018. PubMed ID: 30245029). However, splicing variants in this gene are expected to be pathogenic, and this variant resides in a clinically significant exon (Table S3, DiStefano. 2018. PubMed ID: 30096381). This variant is listed in ClinVar with conflicting interpretations of pathogenic (1); uncertain significance (2); likely benign (1) and benign (1) (https://www.ncbi.nlm.nih.gov/clinvar/variation/48229/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490336	SCV000267430	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2016-03-18	flagged submission	reference population
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University	RCV003984815	SCV004801119	pathogenic	Auditory neuropathy spectrum disorder	2020-03-05	no assertion criteria provided	clinical testing