17-50194032-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000088.4(COL1A1):c.1678G>A(p.Gly560Ser) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G560C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000088.4 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 |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.1678G>A | p.Gly560Ser | missense_variant | 25/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.1480G>A | p.Gly494Ser | missense_variant | 22/48 | ||
COL1A1 | XM_005257058.5 | c.1678G>A | p.Gly560Ser | missense_variant | 25/49 | ||
COL1A1 | XM_005257059.5 | c.958-1339G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.1678G>A | p.Gly560Ser | missense_variant | 25/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000463440.1 | n.68G>A | non_coding_transcript_exon_variant | 3/3 | 2 | ||||
COL1A1 | ENST00000471344.1 | n.710G>A | non_coding_transcript_exon_variant | 8/8 | 2 | ||||
COL1A1 | ENST00000476387.1 | n.27G>A | non_coding_transcript_exon_variant | 1/9 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Apr 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 560 of the COL1A1 protein (p.Gly560Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta types III and IV (PMID: 7691343, 15741671, 17078022, 19751715, 22753364, 24668929, 27510842). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly382Ser. ClinVar contains an entry for this variant (Variation ID: 265433). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265433). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15741671, 17078022, 19751715, 22753364, 24668929, 27510842, 7691343). Different missense changes at the same codon (p.Gly560Arg, p.Gly560Cys) have been reported to be associated with COL1A1 related disorder (ClinVar ID: VCV000526860 / PMID: 2238087, 8799376). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | Aug 24, 2022 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2022 | Occurs in the triple helical domain and replaces a glycine in a 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 (Jovanovic et al., 2021); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G382S) using alternate nomenclature; This variant is associated with the following publications: (PMID: 25944380, 7691343, 17078022, 15741671, 22753364, 26432670, 26177859, 27510842, 30715774, 30692697, 30886339, 31299979, 32981126, 33939306, 28528406, 24668929, 34007986) - |
Osteogenesis imperfecta Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Nov 18, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 13, 2020 | - - |
Ehlers-Danlos syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at