Submissions for variant NM_005422.4(TECTA):c.3743C>T (p.Pro1248Leu)

gnomAD frequency: 0.00029  dbSNP: rs138768918

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454830	SCV000540515	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in 1 proband with HL, at most 1 segregation.
Illumina Laboratory Services, Illumina	RCV001106727	SCV001263822	uncertain significance	Autosomal dominant nonsyndromic hearing loss 12	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001106728	SCV001263823	uncertain significance	Autosomal recessive nonsyndromic hearing loss 21	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375068	SCV001571837	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Supporting, PM2_Supporting
GeneDx	RCV001563123	SCV001786008	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27368438, 24586623, 25262649, 27068579, 30245029, 31554319, 9590290, 21520338, 34008892)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001106728	SCV001976971	pathogenic	Autosomal recessive nonsyndromic hearing loss 21	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PP2, PP3, PP4, PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV001563123	SCV002310459	likely benign	not provided	2024-10-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001563123	SCV005434324	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	TECTA: PM2:Supporting
PreventionGenetics, part of Exact Sciences	RCV004748763	SCV005341890	uncertain significance	TECTA-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The TECTA c.3743C>T variant is predicted to result in the amino acid substitution p.Pro1248Leu. This variant has been reported in individuals with non-syndromic autosomal dominant hearing loss (Table 1, Hildebrand et al. 2011. PubMed ID: 21520338; Shearer et al. 2014. PubMed ID: 25262649; Table S1, Sommen et al. 2016. PubMed ID: 27068579; Table 1, Marinakis et al. 2021. PubMed ID: 34008892). In ClinVar, this variant has conflicting interpretations ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/403527; Table S3, Azaiez et al. 2018. PubMed ID: 30245029). It has also been interpreted as benign based on population frequency in another variant interpretation study (Table S4, Shearer et al. 2014. PubMed ID: 25262649). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.08% of alleles in Ashkenazi Jewish descendants, including 1 homozygote and a total of 518 alleles globally. This population data is not consistent with this variant being a primary cause of autosomal dominant disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.