Submissions for variant NM_194248.3(OTOF):c.3428G>A (p.Arg1143Gln)

gnomAD frequency: 0.00005  dbSNP: rs1330253297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375424	SCV001571953	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Moderate, PP3_Supporting, BP5_Supporting
Ambry Genetics	RCV002547668	SCV003729820	uncertain significance	Inborn genetic diseases	2022-04-08	criteria provided, single submitter	clinical testing	The c.3428G>A (p.R1143Q) alteration is located in exon 28 (coding exon 28) of the OTOF gene. This alteration results from a G to A substitution at nucleotide position 3428, causing the arginine (R) at amino acid position 1143 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001357658	SCV003936590	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357658	SCV001553186	uncertain significance	not provided		no assertion criteria provided	clinical testing	The OTOF p.Arg1143Gln variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs1330253297) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 8 of 277950 chromosomes at a frequency of 0.00002878 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 8 of 127520 chromosomes (freq: 0.000063), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Arg1143 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.