rs777368013
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2
The NM_000093.5(COL5A1):c.2971G>A(p.Gly991Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.2971G>A | p.Gly991Ser | missense_variant | 38/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.2971G>A | p.Gly991Ser | missense_variant | 38/66 | ||
COL5A1 | XM_017014266.3 | c.2971G>A | p.Gly991Ser | missense_variant | 38/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.2971G>A | p.Gly991Ser | missense_variant | 38/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.2971G>A | p.Gly991Ser | missense_variant | 38/66 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251054Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461104Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726870
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, classic type, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | 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 COL5A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the triple helix domain of COL5A1. 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), and variants at these glycine residues in COL5A1 are more frequently observed in individuals with disease than in the general population (PMID: 22696272, 23587214). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. ClinVar contains an entry for this variant (Variation ID: 529239). This missense change has been observed in individual(s) with clinical features of COL5A1-related conditions (Invitae). This variant is present in population databases (rs777368013, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 991 of the COL5A1 protein (p.Gly991Ser). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2022 | The p.G991S variant (also known as c.2971G>A), located in coding exon 38 of the COL5A1 gene, results from a G to A substitution at nucleotide position 2971. The glycine at codon 991 is replaced by serine, an amino acid with similar properties. Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif of the triple helical domain in the COL5A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci.U.S.A. 2008;105:18273-7; Ambry internal data). Glycine substitutions in the triple helical domain of COL5A1 have been reported in association with classic Ehlers-Danlos syndrome (cEDS), but the number of affected individuals is limited and several other COL5A1 glycine substitutions in the triple helical domain (e.g., p.G1078A and p.G1414A) are too common for disease in population databases (Symoens S et al. Hum. Mutat., 2012 Oct;33:1485-93; Ritelli M et al. Orphanet J Rare Dis. 2013 Apr;8:58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at