Submissions for variant NM_005422.4(TECTA):c.5597C>T (p.Thr1866Met)

gnomAD frequency: 0.00001  dbSNP: rs140236996

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000264805	SCV000368223	uncertain significance	Autosomal recessive nonsyndromic hearing loss 21	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000225064	SCV000368224	pathogenic	Autosomal dominant nonsyndromic hearing loss 12	2017-04-27	criteria provided, single submitter	clinical testing	The TECTA c.5597C>T (p.Thr1866Met) missense variant has been reported in four studies in which it is found in a total of 22 patients with hearing loss including in three in a homozygous state, in 15 in a heterozygous state and in four patients from the same family in a heterozygous state with another missense variant in cis as part of a complex allele (Sagong et al. 2010; Hildebrand et al. 2011; Brownstein et al. 2011; Moteki et al. 2012). The p.Thr1866Met variant is thought to be the causative variant from the complex allele. The p.Thr1866Met variant showed segregation with disease in a large Korean family, a large Spanish family and a Jewish family (Sagong et al. 2010; Hildebrand et al. 2011; Brownstein et al. 2011). The three individuals in whom the variant was detected in a homozygous state showed a more severe hearing loss than that of their older relatives carrying the variant in a heterozygous state (Hildebrand et al. 2011). The p.Thr1866Met variant was absent from a total of 594 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on one allele in an area of good sequence coverage so the variant is presumed to be rare. The p.Thr1866Met variant is located in the ZP domain of tectorin, which is highly conserved across species; the Thr1866 residue itself is highly conserved. Based on the collective evidence, the p.Thr1866Met variant is classified as pathogenic for autosomal dominant nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000479439	SCV000568839	pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24006325, 18022253, 22718023, 25413827, 21917145, 21520338, 23891399, 18797289, 17431902, 12746400, 9590290, 9150164, 30935366, 31163360, 32853555, 28000701, 24586623, 31554319, 27627659, 34795337, 34599366, 20947814, 36555390, Miyanohara2024[article], 38224868, 16718611)
Eurofins Ntd Llc (ga)	RCV000479439	SCV000701182	pathogenic	not provided	2016-04-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622759	SCV000741538	likely pathogenic	Inborn genetic diseases	2016-05-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826186	SCV000967729	likely pathogenic	Rare genetic deafness	2018-05-21	criteria provided, single submitter	clinical testing	The p.Thr1866Met variant in TECTA has been reported in 6 individuals with hearin g loss and segregated in >10 affected family members (Brownstein 2011, Hildebran d 2011, Mori 2016, Moteki 2012, Sagong 2010, Su 2014, Zazo Seco 2017). In one f amily, several affected individuals were homozygous for the variant and were rep orted to have a more severe hearing loss than the heterozygotes (Hildebrand 2011 ). This variant has also been reported in ClinVar as Pathogenic/Likely Pathogen ic by four other clinical laboratories (Variation ID# 236058). It has been iden tified in 1/111688 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org; dbSNP rs140236996). Please note that for d iseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population . Computational prediction tools and conservation analysis suggest that the p.Th r1866Met variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is like ly pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000479439	SCV001248731	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000225064	SCV001251503	pathogenic	Autosomal dominant nonsyndromic hearing loss 12		criteria provided, single submitter	research	The TECTA c.5597C>T (p.T1866M) variant has been previously reported in at least 3 families with autosomal dominant nonsyndromic hearing loss. This variant affects a well-conserved amino acid located in the ZP domain of the encoded protein (PMID: 20947814; 21520338; 22718023).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000225064	SCV001368511	pathogenic	Autosomal dominant nonsyndromic hearing loss 12	2020-01-16	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP1_P,PP3.
3billion	RCV000225064	SCV002058957	pathogenic	Autosomal dominant nonsyndromic hearing loss 12	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000236058, PS1_S). The variant was co-segregated with Deafness, autosomal dominant 8/12 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 21520338, 21917145) (PP1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.761, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479439	SCV002239480	pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1866 of the TECTA protein (p.Thr1866Met). This variant is present in population databases (rs140236996, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 20947814, 31163360, 31554319, 32853555). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236058). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TECTA protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV004584374	SCV002578026	likely pathogenic	See cases	2022-09-15	criteria provided, single submitter	clinical testing	ACMG categories: PS5,PM2,PP3,PP5
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000225064	SCV002756432	pathogenic	Autosomal dominant nonsyndromic hearing loss 12	2022-11-10	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000225064	SCV000282008	pathogenic	Autosomal dominant nonsyndromic hearing loss 12	2016-02-19	no assertion criteria provided	research	Congenital, progressive, moderate-profound HL
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000479439	SCV002037533	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000479439	SCV002038330	likely pathogenic	not provided		no assertion criteria provided	clinical testing