Submissions for variant NM_194248.3(OTOF):c.1172del (p.Lys391fs)

dbSNP: rs483353050

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory; Baylor College of Medicine	RCV000119820	SCV000154746	probable-pathogenic	Autosomal recessive nonsyndromic hearing loss 9		criteria provided, single submitter	not provided	Converted during submission to Likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000119820	SCV002784070	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230408	SCV003928737	likely pathogenic	Nonsyndromic genetic hearing loss	2023-04-06	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.1172delA (p.Lys391ArgfsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250524 control chromosomes (gnomAD). c.1172delA has been reported in the literature in an individual affected with auditory neuropathy (example: Tang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003556167	SCV004292101	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys391Argfs*31) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs483353050, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with auditory neuropathy (PMID: 25991456). ClinVar contains an entry for this variant (Variation ID: 133309). For these reasons, this variant has been classified as Pathogenic.