Submissions for variant NM_000393.5(COL5A2):c.437G>A (p.Arg146Gln)

gnomAD frequency: 0.00006  dbSNP: rs144430633

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200613	SCV000250024	uncertain significance	not provided	2018-12-06	criteria provided, single submitter	clinical testing	TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011). p.Arg146Gln (CGA>CAA): c.437 G>A in exon 6 of the COL5A2 gene (NM_000393.3) A variant of unknown significance has been identified in the COL5A2 gene. The R146Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R146Q variant was not observed with any significance in approximately 6,500 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 R146Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD.
Ambry Genetics	RCV002315576	SCV000738745	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-09-13	criteria provided, single submitter	clinical testing	The p.R146Q variant (also known as c.437G>A), located in coding exon 6 of the COL5A2 gene, results from a G to A substitution at nucleotide position 437. The arginine at codon 146 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228870	SCV001230348	benign	Ehlers-Danlos syndrome, classic type, 1	2023-07-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277503	SCV002565844	uncertain significance	Ehlers-Danlos syndrome	2021-04-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492889	SCV002800794	uncertain significance	Ehlers-Danlos syndrome, classic type, 2	2021-10-08	criteria provided, single submitter	clinical testing