Submissions for variant NM_000089.4(COL1A2):c.3430A>C (p.Asn1144His)

dbSNP: rs374282276

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002242643	SCV001565997	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1144 of the COL1A2 protein (p.Asn1144His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. ClinVar contains an entry for this variant (Variation ID: 1060166). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions.
CeGaT Center for Human Genetics Tuebingen	RCV002070242	SCV002497535	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003169895	SCV003861007	uncertain significance	Cardiovascular phenotype	2023-03-08	criteria provided, single submitter	clinical testing	The p.N1144H variant (also known as c.3430A>C), located in coding exon 49 of the COL1A2 gene, results from an A to C substitution at nucleotide position 3430. The asparagine at codon 1144 is replaced by histidine, an amino acid with similar properties. This amino acid position is not 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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003448916	SCV004176283	uncertain significance	Rare disease with thoracic aortic aneurysm and aortic dissection	2023-06-28	criteria provided, single submitter	clinical testing	Heterozygous variant NM_000089:c.3430A>C (p.Asn1144His) in the COL1A2 gene was found on WES data in male proband (6 y.o., Caucasian) with Aortic dissection. An additional rare candidate variant NM_000495:c.3493G>A (p.Glu1165Lys) in the COL4A5 gene (Class III of pathogenicity) was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.000003985 (Date of access 28-06-2023). Clinvar contains entry on this variant (Variation ID: 1060166). This variant has not been reported in any study to our knowledge. Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2.