Submissions for variant NM_000393.5(COL5A2):c.3716A>G (p.His1239Arg)

gnomAD frequency: 0.00001  dbSNP: rs773321546

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196107	SCV000250022	uncertain significance	not provided	2018-01-16	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. The COL5A2 gene encodes for a precursor of type V collagen, which contributes to the structural integrity of various connective tissues, and disruption of COL5A2 function leads to a non-functional alpha-2 (V) chain (Wenstrup et al., 2004). Heterozygous mutations in the COL5A2 gene are associated with Ehlers-Danlos syndrome (EDS), classic type. Approximately 4% of patients with EDS, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011) p.His1239Arg (H1239R) (CAC>CGC): c.3716 A>G in exon 51 of the COL5A2 gene (NM_000393.3) A variant of unknown significance has been identified in the COL5A2 gene. The H1239R variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. This 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. Although this substitution occurs at a position that is conserved in mammals, the H1239R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with EDS, and the H1239R variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of missense mutations occur (Symoens et al., 2012). 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 TAADV2-PANCARD.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853137	SCV002153012	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2021-03-23	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL5A2 protein function. This variant has not been reported in the literature in individuals with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213159). This variant is present in population databases (rs773321546, ExAC no frequency). This sequence change replaces histidine with arginine at codon 1239 of the COL5A2 protein (p.His1239Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine.
Fulgent Genetics, Fulgent Genetics	RCV002478681	SCV002790986	uncertain significance	Ehlers-Danlos syndrome, classic type, 2	2022-03-03	criteria provided, single submitter	clinical testing