Submissions for variant NM_000089.4(COL1A2):c.1268G>A (p.Arg423His)

gnomAD frequency: 0.00005  dbSNP: rs764780528

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000998843	SCV001155144	uncertain significance	not provided	2019-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000998843	SCV001989070	uncertain significance	not provided	2023-12-15	criteria provided, single submitter	clinical testing	Identified in an individual with OI type III and an individual with OI type IV in published literature; of note, the individual with OI type IV also harbored a pathogenic splice site variant in the COL1A2 gene and p.(R423H) was inherited from a healthy parent (PMID: 25944380, 27510842, 28498836); 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28498836, 27510842, 33974636, 30715774, 25944380)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851297	SCV002247542	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-12-03	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 423 of the COL1A2 protein (p.Arg423His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 27510842, 30715774). ClinVar contains an entry for this variant (Variation ID: 425647). 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.
Ambry Genetics	RCV002376891	SCV002685130	uncertain significance	Cardiovascular phenotype	2020-10-26	criteria provided, single submitter	clinical testing	The p.R423H variant (also known as c.1268G>A), located in coding exon 23 of the COL1A2 gene, results from a G to A substitution at nucleotide position 1268. The arginine at codon 423 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in osteogenesis imperfecta cohorts, including type III and type IV cases; however, in one case, this variant was inherited from an unaffected mother, and a de novo COL1A2 splicing mutation was also detected in the proband (Lindahl K et al. Eur J Hum Genet, 2015 Aug;23:1042-50; Li L et al. Hum Mutat, 2019 05;40:588-600). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000998843	SCV005197566	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005034025	SCV005669779	uncertain significance	Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Osteoporosis; Ehlers-danlos syndrome, arthrochalasia type, 2; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2	2024-02-28	criteria provided, single submitter	clinical testing
Department of Medical Sciences, Uppsala University	RCV000490753	SCV000574649	uncertain significance	Osteogenesis imperfecta type III		no assertion criteria provided	clinical testing