rs1114167408
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000088.4(COL1A1):c.563G>A(p.Gly188Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
NM_000088.4 missense
NM_000088.4 missense
Scores
13
2
1
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a compositionally_biased_region Pro residues (size 43) in uniprot entity CO1A1_HUMAN there are 83 pathogenic changes around while only 2 benign (98%) in NM_000088.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ: 3.5319 (greater than the threshold 3.09). Trascript score misZ: 5.7733 (greater than threshold 3.09). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. GenCC has associacion of the gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 17-50198186-C-T is Pathogenic according to our data. Variant chr17-50198186-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50198186-C-T is described in Lovd as [Pathogenic]. Variant chr17-50198186-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COL1A1 | NM_000088.4 | c.563G>A | p.Gly188Asp | missense_variant | 7/51 | ENST00000225964.10 | NP_000079.2 | |
| COL1A1 | XM_011524341.2 | c.563G>A | p.Gly188Asp | missense_variant | 7/48 | XP_011522643.1 | ||
| COL1A1 | XM_005257058.5 | c.563G>A | p.Gly188Asp | missense_variant | 7/49 | XP_005257115.2 | ||
| COL1A1 | XM_005257059.5 | c.563G>A | p.Gly188Asp | missense_variant | 7/38 | XP_005257116.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A1. 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 COL1A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). 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 COL1A1 protein function. ClinVar contains an entry for this variant (Variation ID: 425634). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 27510842). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 188 of the COL1A1 protein (p.Gly188Asp). - |
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 10, 2020 | - - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2019 | The p.G188D variant (also known as c.563G>A), located in coding exon 7 of the COL1A1 gene, results from a G to A substitution at nucleotide position 563. The glycine at codon 188 is replaced by aspartic acid, an amino acid with similar properties. The majority of pathogenic mutations identified to date in COL1A1 have involved the substitution of another amino acid for glycine within the triple-helical domain (Dagleish R. Nucleic Acids Res. 1997 Jan 1;25(1):181-7; Marini JC et al. Hum Mutat. 2007 Mar;28(3):209-21; Bardai G et al. Osteoporos Int 2016 Dec;27(12):3607-3613). This particular glycine substitution has been reported in several osteogenesis imperfecta cohorts (Malfait F et al. Orphanet J Rare Dis, 2013 May;8:78; Lindahl K et al. Eur. J. Hum. Genet., 2015 Aug;23:1042-50). Functional studies in patient fibroblasts suggest that this alteration results in delayed processing of procollagen I into the mature protein (Malfait F et al. Orphanet J Rare Dis, 2013 May;8:78). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL1A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0082);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at