Submissions for variant NM_001365276.2(TNXB):c.9580G>A (p.Asp3194Asn)

gnomAD frequency: 0.00017  dbSNP: rs200036158

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001570310	SCV001794585	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Identified in a patient with a suspected connective tissue disorder in published literature (PMID: 35903967); 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: 35903967)
Ambry Genetics	RCV002386463	SCV002695058	uncertain significance	Cardiovascular phenotype	2024-01-03	criteria provided, single submitter	clinical testing	The p.D3192N variant (also known as c.9574G>A), located in coding exon 27 of the TNXB gene, results from a G to A substitution at nucleotide position 9574. The aspartic acid at codon 3192 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a connective tissue disorders genetic testing cohort (Steinle J et al. Am J Med Genet A, 2022 Oct;188:3016-3023). This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV002476873	SCV002780407	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency; Vesicoureteral reflux 8	2021-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994310	SCV004813177	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: TNXB c.9574G>A (p.Asp3192Asn) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 245962 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TNXB causing Ehlers-Danlos-like syndrome (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.9574G>A has been reported in the literature in at least one individual with a suspected connective tissue disorder (e.g. Steinle_2022, Veatch_2022) . These reports do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos-like syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35903967, 35918752). ClinVar contains an entry for this variant (Variation ID: 1204062). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003399378	SCV004103285	uncertain significance	TNXB-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The TNXB c.9574G>A variant is predicted to result in the amino acid substitution p.Asp3192Asn. This variant was reported as a variant of unknown clinical significance in a next-generation sequencing and analysis of patients referred for connective tissue disorders (Steinle et al. 2022. PubMed ID: 35903967 and Veatch et al. 2022. PubMed ID: 35918752, Supplemental Table 2). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.