Submissions for variant NM_000089.4(COL1A2):c.1420G>A (p.Asp474Asn)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002284763	SCV002574355	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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
Ambry Genetics	RCV002391397	SCV002699775	uncertain significance	Cardiovascular phenotype	2020-01-15	criteria provided, single submitter	clinical testing	The p.D474N variant (also known as c.1420G>A), located in coding exon 25 of the COL1A2 gene, results from a G to A substitution at nucleotide position 1420. The aspartic acid at codon 474 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well 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.
Invitae	RCV003097677	SCV002994982	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2022-09-30	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 COL1A2 protein function. This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. This variant is present in population databases (rs761880600, gnomAD 0.005%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 474 of the COL1A2 protein (p.Asp474Asn).