rs1554807811
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The ENST00000371817.8(COL5A1):c.4654G>A(p.Gly1552Ser) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G1552G) has been classified as Likely benign.
Frequency
Consequence
ENST00000371817.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.4654G>A | p.Gly1552Ser | missense_variant | 61/66 | ENST00000371817.8 | NP_000084.3 | |
LOC101448202 | NR_103451.2 | n.71-3216C>T | intron_variant, non_coding_transcript_variant | |||||
COL5A1 | NM_001278074.1 | c.4654G>A | p.Gly1552Ser | missense_variant | 61/66 | NP_001265003.1 | ||
COL5A1 | XM_017014266.3 | c.4654G>A | p.Gly1552Ser | missense_variant | 61/65 | XP_016869755.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.4654G>A | p.Gly1552Ser | missense_variant | 61/66 | 1 | NM_000093.5 | ENSP00000360882 | P4 | |
COL5A1 | ENST00000371820.4 | c.4654G>A | p.Gly1552Ser | missense_variant | 61/66 | 2 | ENSP00000360885 | A2 | ||
COL5A1 | ENST00000460264.5 | n.122G>A | non_coding_transcript_exon_variant | 2/5 | 3 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 08, 2017 | This sequence change replaces glycine with serine at codon 1552 of the COL5A1 protein (p.Gly1552Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A1-related disease. 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"). 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 missense 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. In summary, this variant is a novel missense change affecting a residue that is critical for protein structure, stability and function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at