Submissions for variant NM_194248.3(OTOF):c.1469C>A (p.Pro490Gln)

dbSNP: rs80356585

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000021034	SCV002769338	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a proline to a glutamine (exon 14). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (P) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (8 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and high conservation. (N) 0600 - Variant is located in the annotated C2 domain (NCBI, PDB, DECIPHER). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternate missense variant at the same residue p.(Pro490Arg) has been reported as likely pathogenic in a family with deafness (PMID: 27652356). (P) 0808 - Previous reports of pathogenicity are conflicting. This variant is reported homozygous in one family and in cis with a likely pathogenic variant p.(Ile515Thr) in another family with deafness (PMID: 12127154, 16371502). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Segregation information for this variant is not currently available. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230370	SCV003928739	uncertain significance	not specified	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.1469C>A (p.Pro490Gln) results in a non-conservative amino acid change located in the C2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250848 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1469C>A has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness with a likely pathogenic variant in cis (OTOF p.Ile515Thr). 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. The following publications have been ascertained in the context of this evaluation (PMID: 12127154). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneReviews	RCV000021034	SCV000041688	not provided	Autosomal recessive nonsyndromic hearing loss 9		no assertion provided	literature only