chr21-45990417-G-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_001848.3(COL6A1):c.997G>T(p.Val333Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V333M) has been classified as Likely benign.
Frequency
Consequence
NM_001848.3 missense
Scores
Clinical Significance
Conservation
Publications
- collagen 6-related myopathyInheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
- Bethlem myopathy 1AInheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
- Ullrich congenital muscular dystrophy 1AInheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- Bethlem myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Ullrich congenital muscular dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.997G>T | p.Val333Leu | missense_variant | Exon 13 of 35 | ENST00000361866.8 | NP_001839.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD4 exome Cov.: 50
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
This variant has not been reported in the literature in individuals affected with COL6A1-related conditions. 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. 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 not expected to disrupt COL6A1 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 333 of the COL6A1 protein (p.Val333Leu). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at