rs67865220
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000089.4(COL1A2):c.1009G>A(p.Gly337Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G337A) has been classified as Pathogenic.
Frequency
Consequence
NM_000089.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.1009G>A | p.Gly337Ser | missense_variant | 19/52 | ENST00000297268.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.1009G>A | p.Gly337Ser | missense_variant | 19/52 | 1 | NM_000089.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461856Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Osteogenesis imperfecta Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change in COL1A2 is predicted to replace glycine with serine at codon 337, p.(Gly337Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in glycine-altering in a Gly-X-Y collagen triple-helical repeat (PMID: 8218237). There is a small physicochemical difference between glycine and serine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in many unrelated individuals with a clinical diagnosis of osteogenesis imperfecta (PMID: 8829649, 33070251). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_VeryStrong, PM1, PM2_Supporting, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 21, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2022 | Glycine substitution within the Gly-X-Y repeat in the collagenous domain of COL1A2; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10942108, 24501682, 32333414, 34367232, 22206639, 27510842, 26138843, 27748872, 16882741, 25944380, 8829649, 21667357, 28810924, 27519266, 28116328, 30715774, 17078022, 9016532, 28498836, 30886339, 32081708, 32166892, 24077912) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | - - |
Osteogenesis imperfecta type III Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Center of Excellence for Medical Genomics, Chulalongkorn University | Jan 06, 2020 | - - |
Ehlers-Danlos syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 24, 2024 | Variant summary: COL1A2 c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change in the Gly-X-Y repeat region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250384 control chromosomes (gnomAD). c.1009G>A has been reported in the literature in individuals affected with Osteogenesis imperfecta (examples: Lindahl_2015, Andersson_2016, Ho Duy_2016). At-least one of these cases was reported as a de novo occurrence (Lindahl_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28498836, PMC4795106, 27519266). ClinVar contains an entry for this variant (Variation ID: 425643). Based on the evidence outlined above, the variant was classified as pathogenic. - |
COL1A2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 01, 2023 | PS4, PM1, PM2, PM5, PP3 - |
Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Mar 09, 2020 | - - |
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 337 of the COL1A2 protein (p.Gly337Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta types I, III, and IV (PMID: 8829649, 21667357, 22206639, 24501682, 25944380, 26138843, 27510842, 27519266, 27748872, 28498836, 28810924). ClinVar contains an entry for this variant (Variation ID: 425643). 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. - |
Ehlers-Danlos syndrome, classic type Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
Ehlers-danlos syndrome, arthrochalasia type, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at