rs72645321
Variant summary
Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000088.4(COL1A1):c.769G>C(p.Gly257Arg) 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G257E) 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 21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.769G>C | p.Gly257Arg | missense_variant | 11/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.769G>C | p.Gly257Arg | missense_variant | 11/48 | ||
COL1A1 | XM_005257058.5 | c.769G>C | p.Gly257Arg | missense_variant | 11/49 | ||
COL1A1 | XM_005257059.5 | c.769G>C | p.Gly257Arg | missense_variant | 11/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.769G>C | p.Gly257Arg | missense_variant | 11/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000495677.1 | n.496G>C | non_coding_transcript_exon_variant | 6/8 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 21, 2021 | 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). 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. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 31447884, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 257 of the COL1A1 protein (p.Gly257Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.