Submissions for variant NM_194248.3(OTOF):c.4463A>T (p.Asp1488Val)

gnomAD frequency: 0.00081  dbSNP: rs142284613

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV002228132	SCV002512113	uncertain significance	Nonsyndromic genetic hearing loss	2021-04-20	reviewed by expert panel	curation	The filtering allele frequency (the lower threshold of the 95% of 49/35,440) of the c.4463A>T (p.Asp1488Val) variant in OTOF is 0.107% for Latino/Admixed American alleles in gnomAD v2, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The REVEL computational prediction tool produced a score of 0.805, which is above the threshold necessary to apply PP3. While this variant has been observed in at least 6 probands with hearing loss, none of these individuals had a second variant identified in OTOF (Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000065239.6). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041544	SCV000065239	uncertain significance	not specified	2021-01-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Asp1488Val variant in the OTOF gene has been identified by our laboratory in 5 individuals with hearing loss, none of whom carried a second pathogenic variant in OTOF. This variant has also been identified in 0.13% (49/35440) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 48235). Computational prediction tools and conservation analyses suggest that the p.Asp1488Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Asp1488Val variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP criteria applied: BS1_Supporting, PP3.
GeneDx	RCV000767001	SCV000620021	uncertain significance	not provided	2021-09-02	criteria provided, single submitter	clinical testing	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
Illumina Laboratory Services, Illumina	RCV001139029	SCV001299135	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2018-01-13	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767001	SCV002047823	uncertain significance	not provided	2020-11-18	criteria provided, single submitter	clinical testing	The OTOF c.4463A>T; p.Asp1488Val variant (rs142284613), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 48235). This variant is found in the Latino population with an allele frequency of 0.14% (49/35,440 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1488 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.805). Due to limited information, the clinical significance of this variant is uncertain at this time.
Invitae	RCV000767001	SCV002177830	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001139029	SCV002791503	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2021-12-14	criteria provided, single submitter	clinical testing