ClinVar Miner

Submissions for variant NM_005422.2(TECTA):c.5597C>T (p.Thr1866Met) (rs140236996)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622759 SCV000741538 likely pathogenic Inborn genetic diseases 2016-05-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000479439 SCV000701182 pathogenic not provided 2016-04-04 criteria provided, single submitter clinical testing
GeneDx RCV000479439 SCV000568839 pathogenic not provided 2017-02-27 criteria provided, single submitter clinical testing The T1866M variant in the TECTA gene has been reported previously in families with autosomal dominant hearing loss (Sagong et al., 2010; Brownstein et al., 2011; Hildebrand et al., 2011). In one family with autosomal dominant hearing loss, 3 individuals were homozygous for the T1866M variant and experienced more severe hearing loss than the heterozygous family members (Hildebrand et al., 2011). The T1866M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1866M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T1866M as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000264805 SCV000368223 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000225064 SCV000368224 pathogenic Deafness, autosomal dominant 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.
Laboratory of Prof. Karen Avraham,Tel Aviv University RCV000225064 SCV000282008 pathogenic Deafness, autosomal dominant 12 2016-02-19 no assertion criteria provided research Congenital, progressive, moderate-profound HL

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