rs764780528
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000089.4(COL1A2):c.1268G>A(p.Arg423His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,599,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R423C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000089.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.1268G>A | p.Arg423His | missense_variant | 23/52 | ENST00000297268.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.1268G>A | p.Arg423His | missense_variant | 23/52 | 1 | NM_000089.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000542 AC: 8AN: 147608Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000902 AC: 21AN: 232794Hom.: 0 AF XY: 0.0000796 AC XY: 10AN XY: 125676
GnomAD4 exome AF: 0.0000454 AC: 66AN: 1452208Hom.: 0 Cov.: 35 AF XY: 0.0000416 AC XY: 30AN XY: 721546
GnomAD4 genome ? AF: 0.0000542 AC: 8AN: 147608Hom.: 0 Cov.: 30 AF XY: 0.0000698 AC XY: 5AN XY: 71604
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2022 | Identified in an individual with OI type III and an individual with OI type IV in published literature (Lindahl et al., 2015; Malmgren et al., 2017; Andersson et al., 2017); 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; 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 (HGMD).; This variant is associated with the following publications: (PMID: 28498836, 27510842, 25944380, 33974636, 30715774) - |
Osteogenesis imperfecta type III Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at