Submissions for variant NM_005422.4(TECTA):c.5836T>C (p.Tyr1946His)

gnomAD frequency: 0.00032  dbSNP: rs144343770

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000787995	SCV000927024	likely benign	Nonsyndromic genetic hearing loss	2019-01-28	reviewed by expert panel	curation	The filtering allele frequency of the c.5836T>C (p.Tyr1946His) variant in the TECTA gene is 0.495% for Ashkenazi Jewish chromosomes by gnomAD (64/10370 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3. The HL EP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case since computational scores are error prone, especially when predicting pathogenicity. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151986	SCV000200544	benign	not specified	2017-05-16	criteria provided, single submitter	clinical testing	p.Tyr1946His in exon 19 of TECTA: This variant is not expected to have clinical significance because it has been identified in 0.6% (62/10152) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs144343770).
Illumina Laboratory Services, Illumina	RCV000288590	SCV000368235	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.
Illumina Laboratory Services, Illumina	RCV000348187	SCV000368236	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000151986	SCV000605349	uncertain significance	not specified	2017-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000827306	SCV000968943	likely benign	not provided	2021-04-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000827306	SCV002380476	likely benign	not provided	2025-01-06	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000827306	SCV005214839	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003917481	SCV004728485	likely benign	TECTA-related disorder	2021-03-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).