chr2-189006354-G-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000090.4(COL3A1):c.3103G>T(p.Gly1035Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1035S) has been classified as Likely 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.3103G>T | p.Gly1035Cys | missense_variant | 43/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.3103G>T | p.Gly1035Cys | missense_variant | 43/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.3004G>T | p.Gly1002Cys | missense_variant | 42/50 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2019 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 1035 of the COL3A1 protein (p.Gly1035Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in an individual affected with Ehlers–Danlos syndrome (PMID: 10706896). This variant is also known as G868C in the literature. ClinVar contains an entry for this variant (Variation ID: 101467). 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 COL3A1, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Collagen Diagnostic Laboratory, University of Washington | - | - - |
Familial aortopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2017 | Variant summary: The COL3A1 c.3103G>T (p.Gly1035Cys) variant involves the alteration of a conserved nucleotide and a critical amino acid. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 246170 control chromosomes in gnomAD. This variant was reported in one ED patient and was associated with arterial complications (Pepin_2000). In addition, one clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at