rs121912925
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000090.4(COL3A1):c.2212G>A(p.Gly738Ser) 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. 12/21 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. G738C) has been classified as Pathogenic.
Frequency
Consequence
NM_000090.4 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 |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.2212G>A | p.Gly738Ser | missense_variant | 31/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.2212G>A | p.Gly738Ser | missense_variant | 31/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.2113G>A | p.Gly705Ser | missense_variant | 30/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Collagen Diagnostic Laboratory, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 26, 2016 | This variant has been reported in individuals and families affected with Ehlers-Danlos syndrome (PMID: 10051163, 24922459). This variant is also known as p.Gly571Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 17227). Glycine residues within the triple helix region are important for fibrillar collagens structure and stability (PMID: 7695699, 19344236). In the case of COL3A1, the majority of the missense substitutions at the triple helix domain affect glycine residues (PMID: 24922459, 25758994). This variant is not present in population databases (rs121912925, ExAC no frequency). This sequence change replaces glycine with serine at codon 738 of the COL3A1 protein (p.Gly738Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 12, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces the glycine in the 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 (HGMD); This variant is associated with the following publications: (PMID: 10706896, 24922459, 9036918, 10051163, 25355833, 29650765) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at