rs1555574496
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000088.4(COL1A1):c.770G>A(p.Gly257Glu) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G257R) has been classified as Pathogenic.
Frequency
Consequence
NM_000088.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.770G>A | p.Gly257Glu | missense_variant | 11/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.770G>A | p.Gly257Glu | missense_variant | 11/48 | ||
COL1A1 | XM_005257058.5 | c.770G>A | p.Gly257Glu | missense_variant | 11/49 | ||
COL1A1 | XM_005257059.5 | c.770G>A | p.Gly257Glu | missense_variant | 11/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.770G>A | p.Gly257Glu | missense_variant | 11/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000495677.1 | n.497G>A | 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
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2016 | This sequence change replaces glycine with glutamic acid at codon 257 of the COL1A1 protein (p.Gly257Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL1A1-related disease. This missense change is located within a functionally conserved triple helix domain of the COL1A1 protein and variants that affect the glycine residue in Gly-Xaa-Yaa repeats of the collagen triple helix are known to disrupt protein folding and stability (PMID: 8218237, 7695699). In summary, this variant is a novel missense change affecting a residue crucial for protein structure and stability. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, glycine substitutions located in COL1A1 triple helix domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at