Submissions for variant NM_194248.3(OTOF):c.5623G>A (p.Val1875Met)

gnomAD frequency: 0.00008  dbSNP: rs370691004

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000354583	SCV000429591	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.
Invitae	RCV001355119	SCV002175133	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001355119	SCV003798883	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355119	SCV001549908	uncertain significance	not provided		no assertion criteria provided	clinical testing	The OTOF p.Val1108Met variant was not identified in the literature nor was it identified in LOVD 3.0, The variant was identified in dbSNP (ID: rs370691004) and ClinVar (classified as uncertain significance by Illumina). The variant was identified in control databases in 32 of 282626 chromosomes at a frequency of 0.0001132 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7222 chromosomes (freq: 0.000277), Latino in 7 of 35426 chromosomes (freq: 0.000198), European (non-Finnish) in 19 of 129016 chromosomes (freq: 0.000147), African in 2 of 24940 chromosomes (freq: 0.00008), East Asian in 1 of 19938 chromosomes (freq: 0.00005) and South Asian in 1 of 30614 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Val1108 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.