Submissions for variant NM_194248.3(OTOF):c.1469C>G (p.Pro490Arg)

dbSNP: rs80356585

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041460	SCV000065155	uncertain significance	not specified	2011-11-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Pro490Arg i n OTOF variant has not been reported in the literature nor previously reported i n the laboratory. This residue is conserved across species and computational ana lyses (biochemical amino acid properties, homology, PolyPhen2, SIFT) suggest tha t the Pro490Arg variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Another variant at the same codon (P ro490Gln) has been reported in one Turkish family with profound hearing loss; ho wever, this variant was observed in cis with a second OTOF missense variant of u nknown significance in that family (Mighomizadeh 2002). The presence of this var iant in combination with a reported pathogenic variant and in this individual wh o has auditory neuropathy, increases the likelihood that the Pro490Arg variant i s pathogenic. In summary, the clinical significance of this variant cannot be de termined at this time; however, based upon the arguments described above, we wou ld lean towards a more likely pathogenic role.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114220	SCV003801308	pathogenic	Nonsyndromic genetic hearing loss	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.1469C>G (p.Pro490Arg) results in a non-conservative amino acid change located in the C2 domain (IPR000008) 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 2e-05 in 250848 control chromosomes (gnomAD). c.1469C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness, including at least one family in which it segregated with the disease phenotype (e.g. Al-Wardy_2016, Zhai_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003430650	SCV004117568	likely pathogenic	OTOF-related condition	2023-06-05	criteria provided, single submitter	clinical testing	The OTOF c.1469C>G variant is predicted to result in the amino acid substitution p.Pro490Arg. This variant has been reported in the homozygous state in individuals with auditory neuropathy (Al-Wardy et al. 2016. PubMed ID: 27652356; Zhai et al. 2020. PubMed ID: 33426078; Table S1A, Thorpe et al. 2021. PubMed ID: 34424407). Of note, another variant impacting the same amino acid (p.Pro490Gln) was reported in cis with another variant in OTOF (p.Ile515Thr), both in the homozygous state in four individuals from the same family all with nonsyndromic autosomal recessive deafness (Mirghomizadeh et al. 2002. PubMed ID: 12127154). The c.1469C>G (p.Pro490Arg) variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-26705384-G-C). This variant is interpreted as likely pathogenic.
Invitae	RCV003556115	SCV004292098	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 490 of the OTOF protein (p.Pro490Arg). This variant is present in population databases (rs80356585, gnomAD 0.004%). This missense change has been observed in individuals with auditory neuropathy spectrum disorder and/or deafness (PMID: 27652356, 33426078, 33908410, 34424407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48170). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. For these reasons, this variant has been classified as Pathogenic.