rs67707918
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000089.4(COL1A2):c.1171G>A(p.Gly391Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,570 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G391C) has been classified as Pathogenic.
Frequency
Consequence
NM_000089.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.1171G>A | p.Gly391Ser | missense_variant | 21/52 | ENST00000297268.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.1171G>A | p.Gly391Ser | missense_variant | 21/52 | 1 | NM_000089.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.16e-7 AC: 1AN: 1397570Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 689306
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Osteogenesis imperfecta Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 05, 2020 | - - |
Dentinogenesis imperfecta Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Dental Genetics Laboratory, Seoul National University School of Dentistry | - | - - |
Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2022 | Observed in patients with osteogenesis imperfecta (OI) type IV or mild OI, some with dentinogenesis imperfecta, in published literature (Marini et al., 2007; Lindahl et al., 2015; Malmgren et al., 2017; Harvengt al., 2019); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26177859, 17078022, 25944380, 30152103, 30886339, Lee2021[Publication], 23227268, 27510842, 34201399, 24077912) - |
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 391 of the COL1A2 protein (p.Gly391Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant COL1A2-related conditions (PMID: 17078022, 23227268, 27510842, 30152103, 30886339). This variant is also known as p.Gly301Ser. ClinVar contains an entry for this variant (Variation ID: 425645). 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 expected to disrupt COL1A2 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at