Submissions for variant NM_000089.4(COL1A2):c.2456G>A (p.Arg819His)

gnomAD frequency: 0.00008  dbSNP: rs773985005

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000344148	SCV000470607	likely benign	Ehlers-danlos syndrome, arthrochalasia type, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000394670	SCV000470608	uncertain significance	Osteogenesis imperfecta	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002229912	SCV000938300	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-01-17	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 819 of the COL1A2 protein (p.Arg819His). This variant is present in population databases (rs773985005, gnomAD 0.02%). This missense change has been observed in individual(s) with aortic dissection and/or osteogenesis imperfecta (PMID: 25944380, 34422331). ClinVar contains an entry for this variant (Variation ID: 360962). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL1A2 protein function. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262348	SCV001440175	uncertain significance	Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429326	SCV002731593	uncertain significance	Cardiovascular phenotype	2023-04-20	criteria provided, single submitter	clinical testing	The p.R819H variant (also known as c.2456G>A), located in coding exon 40 of the COL1A2 gene, results from a G to A substitution at nucleotide position 2456. The arginine at codon 819 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in an individual with osteogenesis imperfecta, however additional variants were identified and clinical details were limited (Lindahl K et al. Eur J Hum Genet, 2015 Aug;23:1042-50). This alteration has also been reported in a ostensibly healthy control (Chen ZR et al. J Thorac Dis, 2021 Jul;13:4008-4022). 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.
GeneDx	RCV003159117	SCV003853013	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Has been reported in two patients with thoracic aortic aneurysm disease (TAAD) (Chen et al., 2021); 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 (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34422331)