Submissions for variant NM_001365276.2(TNXB):c.2461C>T (p.Arg821Ter)

gnomAD frequency: 0.00002  dbSNP: rs749890642

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413590	SCV000492016	likely pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing	The R821X variant in the TNXB gene has been reported previously in two brothers with features of Ehlers-Danlos syndrome including joint hypermobility, joint dislocations, and velvety hyperextensible skin (Demiridas et al., 2016). Both individuals also harbored a second variant in TNXB however it was not clear from the report whether it was confirmed that these occurred on opposite alleles (in trans) (Demirdas et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R821X variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R821X variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
MGZ Medical Genetics Center	RCV002288987	SCV002580851	likely pathogenic	Ehlers-Danlos syndrome due to tenascin-X deficiency	2022-02-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343804	SCV004067782	pathogenic	Cardiovascular phenotype	2023-08-08	criteria provided, single submitter	clinical testing	The p.R821* pathogenic mutation (also known as c.2461C>T), located in coding exon 4 of the TNXB gene, results from a C to T substitution at nucleotide position 2461. This changes the amino acid from an arginine to a stop codon within coding exon 4. This variant has been reported to co-occur with other TNXB alterations in individuals with features of classic-like EDS (Demirdas S et al. Clin Genet, 2017 Mar;91:411-425; Green C et al. Genet Med, 2020 Oct;22:1576-1582). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This pathogenic alteration is expected to cause autosomal recessive classic-like EDS when detected with a second pathogenic or likely pathogenic variant on the other allele. However, although haploinsufficiency of TNXB has been reported in association with hypermobility in females (Zweers MC, et al. Am J Hum Genet. 2003; 73(1):217-7), a causal relationship has not been established and its clinical significance in the heterozygous state is unclear.
PreventionGenetics, part of Exact Sciences	RCV003401402	SCV004104276	pathogenic	TNXB-related disorder	2022-08-21	criteria provided, single submitter	clinical testing	The TNXB c.2461C>T variant is predicted to result in premature protein termination (p.Arg821*). This variant has been previously reported in the compound heterozygous state in individuals with Ehlers-Danlos syndrome (Demirdas et al. 2017. PubMed ID: 27582382; Green et al. 2020. PubMed ID: 32572181, Supplementary Table S1). This variant is reported in 0.0045% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-32057054-G-A). Nonsense variants in TNXB are expected to be pathogenic. This variant is interpreted as pathogenic.
Institute of Immunology and Genetics Kaiserslautern	RCV002288987	SCV005077733	pathogenic	Ehlers-Danlos syndrome due to tenascin-X deficiency	2024-06-28	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM3, PM2_P, PP5; Variant was found in heterozygous state (carrier status)
3billion	RCV002288987	SCV005905545	pathogenic	Ehlers-Danlos syndrome due to tenascin-X deficiency	2023-10-17	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000373424 /PMID: 27582382). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000413590	SCV001807822	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413590	SCV001972235	pathogenic	not provided		no assertion criteria provided	clinical testing