rs72667029
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000088.4(COL1A1):c.599G>T(p.Gly200Val) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G200S) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
NM_000088.4 missense
NM_000088.4 missense
Scores
13
1
2
Clinical Significance
Conservation
PhyloP100: 5.99
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 19 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_000088.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-50197993-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2780397.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, COL1A1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
?
Variant 17-50197992-C-A is Pathogenic according to our data. Variant chr17-50197992-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50197992-C-A is described in Lovd as [Pathogenic]. Variant chr17-50197992-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.599G>T | p.Gly200Val | missense_variant | 8/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.599G>T | p.Gly200Val | missense_variant | 8/48 | ||
COL1A1 | XM_005257058.5 | c.599G>T | p.Gly200Val | missense_variant | 8/49 | ||
COL1A1 | XM_005257059.5 | c.599G>T | p.Gly200Val | missense_variant | 8/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.599G>T | p.Gly200Val | missense_variant | 8/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000495677.1 | n.326G>T | non_coding_transcript_exon_variant | 3/8 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, arthrochalasia type Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.599G>T(p.Gly200Val) variant in COL1A1 gene has been reported previously in heterozygous state in individual(s) affected with COL1A1-related disorders (Balasubramanian M, et. al., 2015). The p.Gly200Val variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Gly200Val in COL1A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 200 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2019 | - - |
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2021 | This variant has been reported in individuals affected with osteogenesis imperfecta (PMID: 18670065, 25436829). For these reasons, this variant has been classified as Pathogenic. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 200 of the COL1A1 protein (p.Gly200Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. - |
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
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of sheet (P = 0.0266);
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