21-45990792-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001848.3(COL6A1):c.1022G>A(p.Gly341Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G341C) has been classified as Pathogenic.
Frequency
Consequence
NM_001848.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.1022G>A | p.Gly341Asp | missense_variant | Exon 14 of 35 | ENST00000361866.8 | NP_001839.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly341 amino acid residue in COL6A1. Other variant(s) that disrupt this residue have been observed in individuals with COL6A1-related conditions (PMID: 15689448, 15955946, 26436962; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant disrupts the triple helix domain of COL6A1. 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 COL6A1, variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). 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 COL6A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17172). This missense change has been observed in individuals with autosomal dominant collagenopathies (PMID: 11865138; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 341 of the COL6A1 protein (p.Gly341Asp). -
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not provided Pathogenic:1
COL6A1: PM1:Strong, PM2, PM5, PM6, PS4:Moderate, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at