Submissions for variant NM_005422.4(TECTA):c.5114A>G (p.Tyr1705Cys)

gnomAD frequency: 0.00001  dbSNP: rs886047844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000320738	SCV000368207	uncertain significance	Autosomal dominant nonsyndromic hearing loss 12	2018-01-12	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.
Illumina Laboratory Services, Illumina	RCV000379983	SCV000368208	uncertain significance	Autosomal recessive nonsyndromic hearing loss 21	2018-01-12	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.
Ambry Genetics	RCV002520682	SCV003671632	uncertain significance	Inborn genetic diseases	2022-12-05	criteria provided, single submitter	clinical testing	The c.5114A>G (p.Y1705C) alteration is located in exon 15 (coding exon 15) of the TECTA gene. This alteration results from a A to G substitution at nucleotide position 5114, causing the tyrosine (Y) at amino acid position 1705 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001354338	SCV003837353	uncertain significance	not provided	2022-08-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354338	SCV001548933	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TECTA p.Tyr1705Cys variant was not identified in the literature but was identified in dbSNP (ID: rs886047844) and ClinVar (classified as uncertain significance by Illumina for Recessive Nonsyndromic Hearing Loss and Dominant Nonsyndromic Hearing Loss). The variant was identified in control databases in 1 of 251476 chromosomes at a frequency of 0.000003977 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the Ashkenazi Jewish population in 1 of 10080 chromosomes (freq: 0.000099), but was not observed in the African, Latino, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Tyr1705 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.