17-50197757-C-A
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000088.4(COL1A1):c.671G>T(p.Gly224Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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. G224S) has been classified as Pathogenic.
Frequency
Consequence
NM_000088.4 missense
Scores
Clinical Significance
Conservation
Publications
- Caffey diseaseInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
- combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
- Ehlers-Danlos syndromeInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- Ehlers-Danlos syndrome, arthrochalasia typeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- osteogenesis imperfecta type 1Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- osteogenesis imperfecta type 2Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- osteogenesis imperfecta type 3Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- osteogenesis imperfecta type 4Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
- Ehlers-Danlos syndrome, classic type, 1Inheritance: AD Classification: MODERATE Submitted by: ClinGen
- Ehlers-Danlos syndrome, classic typeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Ehlers-Danlos/osteogenesis imperfecta syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- high bone mass osteogenesis imperfectaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.671G>T | p.Gly224Val | missense_variant | Exon 9 of 51 | ENST00000225964.10 | NP_000079.2 | |
COL1A1 | XM_011524341.2 | c.671G>T | p.Gly224Val | missense_variant | Exon 9 of 48 | XP_011522643.1 | ||
COL1A1 | XM_005257058.5 | c.671G>T | p.Gly224Val | missense_variant | Exon 9 of 49 | XP_005257115.2 | ||
COL1A1 | XM_005257059.5 | c.671G>T | p.Gly224Val | missense_variant | Exon 9 of 38 | XP_005257116.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The G224V pathogenic variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. G224V occurs in the triple helical domain and replaces the Glycine in the canonical Gly-X-Y repeat. Variants in these Glycines result in poor winding of the collagen triple helix and a less functional protein. The G224V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G224V variant occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby Glycine residues (G224S/C, G221S/C/A, G239D) have been reported in the Human Gene Mutation Database in association with COL1A1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of this pathogenic variant is consistent with the diagnosis of a COL1A1-related skeletal dysplasia -
Osteogenesis imperfecta type I Pathogenic:1
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). In summary, this variant is a novel missense change affecting a residue that is known to be critical for normal protein structure, stability and function. This type of missense change is also highly enriched in affected individuals and expected to be pathogenic. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with a COL1A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 224 of the COL1A1 protein (p.Gly224Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at