Submissions for variant NM_194248.3(OTOF):c.1630C>T (p.Arg544Cys)

gnomAD frequency: 0.00093  dbSNP: rs139954767

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041467	SCV000065162	uncertain significance	not specified	2018-08-21	criteria provided, single submitter	clinical testing	The p.Arg544Cys variant in OTOF has been identified in 1 individual with autosom al recessive sensorineural hearing loss who carried a second OTOF variant of unc ertain significance; it is unclear whether these variants are in trans (Sommen 2 016). The p.Arg544Cys variant has also been identified by our laboratory in 6 in dividuals with hearing loss; however, none of these individuals carried a varian t affecting the other copy of the OTOF gene or was reported to have auditory neu ropathy typically associated with OTOF related hearing loss. This variant has be en reported in ClinVar (Variation ID: 48176). It has been identified in 0.15% (1 93/125430) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal ysis suggest that the p.Arg544Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, the c linical significance of the p.Arg544Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, BS1_Supporting.
Illumina Laboratory Services, Illumina	RCV000357820	SCV000429634	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2018-01-12	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.
Eurofins Ntd Llc (ga)	RCV000726979	SCV000704632	uncertain significance	not provided	2016-12-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000726979	SCV001144806	uncertain significance	not provided	2019-05-14	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375443	SCV001572020	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PP3_Supporting
GeneDx	RCV000726979	SCV001871342	uncertain significance	not provided	2022-03-07	criteria provided, single submitter	clinical testing	Observed in a patient with hearing loss in published literature (Sommen 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: 34426522, 27068579)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726979	SCV002236987	likely benign	not provided	2024-10-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000357820	SCV002775350	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2022-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041467	SCV003844738	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.1630C>T (p.Arg544Cys) results in a non-conservative amino acid change located in the Ferlin, third C2 domain (IPR037722) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 249668 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00077 vs 0.0011), allowing no conclusion about variant significance. c.1630C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss without evidence of cosegregation (Kothiyal_2010, Sommen_2016). These reports 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. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variants as likely benign (n=1) or uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000726979	SCV005434578	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	OTOF: PP3