rs1060500194
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate
The NM_000090.4(COL3A1):c.1196G>C(p.Gly399Ala) variant causes a missense, splice region 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. 14/22 in silico tools predict a damaging outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. 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. G399D) has been classified as Pathogenic.
Frequency
Consequence
NM_000090.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.1196G>C | p.Gly399Ala | missense_variant, splice_region_variant | 18/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.1196G>C | p.Gly399Ala | missense_variant, splice_region_variant | 18/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.1097G>C | p.Gly366Ala | missense_variant, splice_region_variant | 17/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2018 | This sequence change replaces glycine with alanine at codon 399 of the COL3A1 protein (p.Gly399Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. 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 COL3A1 TH domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic. Glycine residues within the triple helix (TH) domain are important for fibrillar collagens structure and stability (PMID: 7695699, 8218237, 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 (ExAC no frequency) and has not been reported in the literature in individuals with a COL3A1-related disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at