Submissions for variant NM_001365276.2(TNXB):c.12469+2T>C

gnomAD frequency: 0.01022  dbSNP: rs545719209

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519700	SCV000618266	uncertain significance	not provided	2021-10-25	criteria provided, single submitter	clinical testing	Canonical splice site variant with an unclear effect on protein function; Observed in the heterozygous state in individuals with clinical features of EhlersDanlos syndrome and a diagnosis of congenital adrenal hyperplasia (Lao et al., 2021); This variant is associated with the following publications: (PMID: 33332743)
Baylor Genetics	RCV003333074	SCV004041488	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency	2023-08-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003333074	SCV004047313	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency		criteria provided, single submitter	clinical testing	The splice donor variant c.12469+2T>C in TNXB (NM_001365276.2) has been reported previously in heterozygous state in individuals with clinical features of EhlersDanlos syndrome and a diagnosis of congenital adrenal hyperplasia ( Lao et al, 2021 ) . The c.12469+2T>C variant is observed in 64/2,496 (2.5641%) alleles from individuals of Ashkenazi Jewish background in gnomAD Exomes. This variant mutates a splice-donor sequence, potentially resulting in the retention of large segments of intronic DNA by the mRNA and nonfunctional proteins. The c.12469+2T>C variant is a loss of function variant in the gene TNXB, which is intolerant of Loss of Function variants. The nucleotide change in TNXB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000519700	SCV004227207	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing	BS1, BP4, BP7, PS3_supporting, PVS1_strong
PreventionGenetics, part of Exact Sciences	RCV003979934	SCV004795348	uncertain significance	TNXB-related disorder	2023-12-03	criteria provided, single submitter	clinical testing	The TNXB c.12463+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported to be associated with a moderate hypermobility Ehlers-Danlos syndrome (EDS) phenotype in the affected congenital adrenal hyperplasia (CAH) patients due to a reduced splicing efficiency at TNXB intron 42 (Lao et al. 2020. PubMed ID: 33332743). This variant was also reported in an individual with congenital anomalies of the kidney and urinary tract (Table S3, Rao. 2019. PubMed ID: 31328266). In the gnomAD variant database based on next-generation sequencing technology, the highest minor allele frequency of this variant has been found at ~2.7% in Ashkenazi Jewish and 2.5% in South Asian with one homozygous individual documented; however, this may not be an accurate indication of its allele frequency because it is located in a highly homologous region (exons 32 to 44) of the gene and there are limitations of current capture-based short-read next-generation sequencing technology to sequence this type of homologous sequence (Mandelker et al. 2016. PubMed ID: 27228465). Of note, at PreventionGenetics, we have previously found this variant in several unrelated patients, at least one of whom inherited this variant from an unaffected mother. In summary, the clinical significance of this variant is still uncertain due to insufficient evidence.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003333074	SCV004806630	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency	2024-03-26	criteria provided, single submitter	clinical testing