Submissions for variant NM_001365276.2(TNXB):c.3322G>A (p.Val1108Met)

gnomAD frequency: 0.00061  dbSNP: rs121912575

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480037	SCV000568776	likely benign	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15733269, 25333069, 20853426, 27989960)
Molecular Genetics, Royal Melbourne Hospital	RCV002051617	SCV002503633	uncertain significance	Ehlers-Danlos syndrome due to tenascin-X deficiency	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace valine with methionine at codon 1108 of the TNXB protein, p.(Val1108Met), also known as p.(Val1195Met). The valine residue is lowly conserved with methionine present in at least two vertebrates (100 vertebrates, UCSC), and is located in the fibronectin type-III 2 domain. There is a small physicochemical difference between valine and methionine. The variant is present in a large population cohort at a frequency of 0.08% (rs121912575, 221/275,544 alleles, 1 homozygote in gnomAD v2.1), with an allele frequency of 1% in the Ashkenazi Jewish population (98/10,232 alleles, 1 homozygote). The variant has been identified heterozygous (with no other TNXB variant detected) in a single hypermobility-type Ehlers-Danlos syndrome case with normal TNX serum levels and a significant increase in elastic fibre length in a skin biopsy (PMID: 15733269). It has also been identified in centenarians (PMID: 25333069). In molecular polypeptide analyses the variant does not alter three dimensional structure and demonstrates mild destabilization effects on the thermodynamic and mechanical stability (PMID: 20853426). The variant has previously been reported as a variant of uncertain significance (LOVD). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. No criteria are met.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251892	SCV002522881	uncertain significance	See cases	2021-11-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276540	SCV002566244	uncertain significance	Ehlers-Danlos syndrome	2021-07-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453251	SCV002611649	likely benign	Cardiovascular phenotype	2022-10-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic	RCV000480037	SCV004227222	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	BS1
OMIM	RCV002051617	SCV000029300	pathogenic	Ehlers-Danlos syndrome due to tenascin-X deficiency	2005-04-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003914821	SCV004733919	likely benign	TNXB-related disorder	2023-07-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).