Submissions for variant NM_005422.4(TECTA):c.4085G>A (p.Trp1362Ter)

gnomAD frequency: 0.00011  dbSNP: rs199638531

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089678	SCV001245162	pathogenic	Nonsyndromic genetic hearing loss	2020-01-21	reviewed by expert panel	curation	The c.4085G>A (p.Trp1362Ter) nonsense variant in TECTA is predicted to cause a premature stop codon in biologically-relevant exon 11 of 23 total exons, leading to a truncated or absent protein in a gene in which loss of function is an established mechanism of autosomal recessive nonsyndromic hearing loss (PVS1; PMID: 30192042). This variant is present in 0.01121% (14/124864) of non-Finnish European chromosomes in gnomAD v2 (PM2_Supporting). It has been observed in at least two probands presenting with nonsyndromic hearing loss (PMID: 31163360; LMM internal data SCV000711208.2). One individual harbored another nonsense variant in TECTA, which was suspected to be pathogenic (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting.
Eurofins Ntd Llc (ga)	RCV000593220	SCV000703594	pathogenic	not provided	2016-12-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602678	SCV000711208	likely pathogenic	Rare genetic deafness	2018-12-04	criteria provided, single submitter	clinical testing	The p.Trp1362X variant in TECTA has been identified in the heterozygous state in 1 family with hearing loss; however, this family also harbored pathogenic varia nts in different genes that may explain their hearing loss (LMM data). The p.Trp 1362X variant has also been identified in 0.01% (14/124864) of European chromoso mes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVa r (Variation ID 498538). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This nonsense variant leads to a premature termination codon at positio n 1362, which is predicted to lead to a truncated or absent protein. Loss of fun ction of the TECTA gene is an established disease mechanism in autosomal recessi ve hearing loss (Hildebrand 2011). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PVS1, PM2_Supporting. Please note that some truncating variant s in TECTA have been reported to segregate in an autosomal dominant manner (Coli n 2008, Hildebrand 2011); however, there is currently insufficient data to predi ct whether the p.Trp1362X variant can lead to dominantly inherited hearing loss.
Illumina Laboratory Services, Illumina	RCV000778309	SCV000914492	uncertain significance	Autosomal dominant nonsyndromic hearing loss 12	2017-04-28	criteria provided, single submitter	clinical testing	The TECTA c.4085G>A (p.Trp1362Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for a dominant form of nonsyndromic hearing loss.
Illumina Laboratory Services, Illumina	RCV000778310	SCV000914493	uncertain significance	Autosomal recessive nonsyndromic hearing loss 21	2017-04-28	criteria provided, single submitter	clinical testing	The TECTA c.4085G>A (p.Trp1362Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for a recessive form of nonsyndromic hearing loss.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000593220	SCV001584375	pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1362*) in the TECTA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TECTA are known to be pathogenic (PMID: 11087000, 12746400, 17431902, 24130743). This variant is present in population databases (rs199638531, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 31163360). ClinVar contains an entry for this variant (Variation ID: 498538). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000593220	SCV001829314	likely pathogenic	not provided	2022-11-16	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31163360)