ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.5816G>A (p.Arg1939Gln)

gnomAD frequency: 0.00004  dbSNP: rs80356605
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Revvity Omics, Revvity RCV000021073 SCV002020586 pathogenic Autosomal recessive nonsyndromic hearing loss 9 2019-12-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV003480023 SCV004225723 pathogenic not provided 2022-08-14 criteria provided, single submitter clinical testing PP3, PM2_supporting
Invitae RCV003480023 SCV004344015 pathogenic not provided 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1939 of the OTOF protein (p.Arg1939Gln). This variant is present in population databases (rs80356605, gnomAD 0.07%). This missense change has been observed in individual(s) with auditory neuropathy spectrum disorder and/or deafness (PMID: 23562982, 34536124). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese ancestry (PMID: 22575033, 34424407, 34536124). This variant is also known as c.3515G>A (p.Arg1172Gln). ClinVar contains an entry for this variant (Variation ID: 6136). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg1939 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been observed in individuals with OTOF-related conditions (PMID: 34536124), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006510 SCV000026693 pathogenic Auditory neuropathy, autosomal recessive, 1 2003-01-01 no assertion criteria provided literature only
GeneReviews RCV000021073 SCV000041730 not provided Autosomal recessive nonsyndromic hearing loss 9 no assertion provided literature only
Baylor Genetics RCV000021073 SCV000328831 uncertain significance Autosomal recessive nonsyndromic hearing loss 9 2014-10-21 no assertion criteria provided clinical testing Our laboratory reported three molecular diagnoses in OTOF (NM_004802.3, c.3515G>A), SLC12A6 (NM_001042494.1, c.73dup) and USH2A (NM_206933.2, c.13709G>A and c.5858C>G in trans), in one individual with reported features of congenital deafness, autism, delayed speech, macrocephaly, and skin anomalies that include hyperpigmented areas, excessively stretchy skin, poor wound healing, and keloids. Heterozygotes for this variant would be expected to be asymptomatic carriers.

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