Submissions for variant NM_194248.3(OTOF):c.5405C>T (p.Ala1802Val)

gnomAD frequency: 0.00011  dbSNP: rs144562626

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV002240656	SCV002512135	uncertain significance	Nonsyndromic genetic hearing loss	2021-06-16	reviewed by expert panel	curation	The REVEL computational prediction analysis tool produced a score of 0.729 for the c.5405C>T (p.Ala1802Val) variant in OTOF, which is above the threshold necessary to apply PP3, and the amino acid residue is well conserved in UCSC (PP3). This variant has been detected in 3 patients with hearing loss. For 2 of those patients, this variant was observed compound heterozygous with rare but unknown variants, and in 1 the variant was observed in the heterozygous state along with heterozygous variants in other hearing loss related genes. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3.
Illumina Laboratory Services, Illumina	RCV001141524	SCV001301875	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195508	SCV001365886	uncertain significance	not specified	2020-02-11	criteria provided, single submitter	clinical testing	The p.Ala1802Val variant in OTOF has been reported in 7 alleles from a cohort of Japanese individuals with hearing loss, including two compound heterozygotes with a second variant of uncertain significance in OTOF, though it was not clear if phasing was performed (Iwasa 2019). It has also been identified in 0.05% (10/19952) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
CeGaT Center for Human Genetics Tuebingen	RCV003413950	SCV004138745	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	OTOF: PM2, PM3