Submissions for variant NM_000393.5(COL5A2):c.1579C>T (p.Arg527Cys) (rs863223490)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199532	SCV000249958	uncertain significance	not provided	2017-09-21	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.Arg527Cys (CGT>TGT): c.1579 C>T in exon 24 of the COL5A2 gene (NM_000393.3). A variant of unknown significance has been identified in the COL5A2 gene. The R527C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R527C variant was not observed 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 R527C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This result cannot be interpreted for diagnosis or used for family member screening at this time. This variant was found in TAADV2-1,COL5A2.
Invitae	RCV000634625	SCV000755957	uncertain significance	Ehlers-Danlos syndrome, classic type	2018-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 527 of the COL5A2 protein (p.Arg527Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213097). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.