Submissions for variant NM_001365276.2(TNXB):c.7750C>T (p.Arg2584Cys)

gnomAD frequency: 0.00096  dbSNP: rs201690494

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001658885	SCV001874075	uncertain significance	not provided	2024-07-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
CeGaT Center for Human Genetics Tuebingen	RCV001658885	SCV002545407	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	TNXB: BP4
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276852	SCV002566326	uncertain significance	Ehlers-Danlos syndrome	2022-07-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002414292	SCV002674645	uncertain significance	Cardiovascular phenotype	2024-03-08	criteria provided, single submitter	clinical testing	The p.R2584C variant (also known as c.7750C>T), located in coding exon 21 of the TNXB gene, results from a C to T substitution at nucleotide position 7750. The arginine at codon 2584 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224575	SCV003920582	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency; Vesicoureteral reflux 8	2022-04-14	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in 0.2% (30/15282) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-32058133-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 1254703). Evoluationary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Breakthrough Genomics, Breakthrough Genomics	RCV001658885	SCV005188866	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001658885	SCV005198831	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005057541	SCV005725571	uncertain significance	not specified	2024-11-27	criteria provided, single submitter	clinical testing	Variant summary: TNXB c.7750C>T (p.Arg2584Cys) results in a non-conservative amino acid change located in the Fibronectin type-III domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 1612668 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TNXB causing Ehlers-Danlos syndrome due to tenascin-X deficiency (0.00082 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7750C>T in individuals affected with Ehlers-Danlos syndrome due to tenascin-X deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1254703). Based on the evidence outlined above, the variant was classified as uncertain significance.