Submissions for variant NM_000089.4(COL1A2):c.2465G>A (p.Arg822His)

gnomAD frequency: 0.00006  dbSNP: rs1800240

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002241120	SCV001387539	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 822 of the COL1A2 protein (p.Arg822His). This variant is present in population databases (rs1800240, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 945199). 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 COL1A2 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001538376	SCV001756016	uncertain significance	not provided	2020-11-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 945199; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Stenson et al., 2014)
PreventionGenetics, part of Exact Sciences	RCV003928789	SCV004737459	uncertain significance	COL1A2-related disorder	2023-12-20	criteria provided, single submitter	clinical testing	The COL1A2 c.2465G>A variant is predicted to result in the amino acid substitution p.Arg822His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004033978	SCV005032272	uncertain significance	Cardiovascular phenotype	2023-09-29	criteria provided, single submitter	clinical testing	The p.R822H variant (also known as c.2465G>A), located in coding exon 40 of the COL1A2 gene, results from a G to A substitution at nucleotide position 2465. The arginine at codon 822 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.