Submissions for variant NM_001365276.2(TNXB):c.11227G>A (p.Asp3743Asn)

gnomAD frequency: 0.00082  dbSNP: rs1254121532

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001270709	SCV001451453	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency	2019-06-26	criteria provided, single submitter	clinical testing	The TNXB c.11221G>A (p.Asp3741Asn) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.002238 in the Other population from the Genome Aggregation Database. Based on the limited evidence, the p.Asp3741Asn variant is classified as a variant of uncertain significance for Ehlers-Danlos syndrome due to tenascin-X deficiency.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276672	SCV002566183	uncertain significance	Ehlers-Danlos syndrome	2020-08-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987821	SCV004804367	likely benign	not specified	2024-01-10	criteria provided, single submitter	clinical testing	Variant summary: TNXB c.11221G>A (p.Asp3741Asn) results in a conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 435730 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0), including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is above the estimated maximal expected allele frequency for a pathogenic variant in TNXB causing Ehlers-Danlos-like syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.11575G>A has been reported in the literature in individuals affected with Primary Vesicoureteric Reflux (Elahi_2016). This report does 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 publication have been ascertained in the context of this evaluation (PMID: 26408188). ClinVar contains an entry for this variant (Variation ID: 989243). Based on the evidence outlined above, the variant was classified as likely benign.