rs886043576
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_004369.4(COL6A3):c.6890G>C(p.Gly2297Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2297R) has been classified as Uncertain significance.
Frequency
Consequence
NM_004369.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.6890G>C | p.Gly2297Ala | missense_variant | 29/44 | ENST00000295550.9 | |
COL6A3 | NM_057167.4 | c.6272G>C | p.Gly2091Ala | missense_variant | 28/43 | ||
COL6A3 | NM_057166.5 | c.5069G>C | p.Gly1690Ala | missense_variant | 26/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A3 | ENST00000295550.9 | c.6890G>C | p.Gly2297Ala | missense_variant | 29/44 | 1 | NM_004369.4 | P1 | |
COL6A3 | ENST00000472056.5 | c.5069G>C | p.Gly1690Ala | missense_variant | 26/41 | 1 | |||
COL6A3 | ENST00000353578.9 | c.6272G>C | p.Gly2091Ala | missense_variant | 28/43 | 5 | |||
COL6A3 | ENST00000491769.1 | n.1144G>C | non_coding_transcript_exon_variant | 6/20 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 12, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 29, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 28, 2023 | - - |
COL6A3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 01, 2023 | The COL6A3 c.6890G>C variant is predicted to result in the amino acid substitution p.Gly2297Ala. This variant has been reported in the heterozygous state in two individuals with unusual progressive limb girdle muscular dystrophy 2A (Table S1, Nallamilli et al. 2018. PubMed ID: 30564623). Both individuals also harbored a homozygous pathogenic variant in the CAPN3 gene. It has also been reported in a male individual from a preconception carrier screening study (Table S1, Capalbo et al. 2019. PubMed ID: 31589614). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant occurs in the conserved Gly-X-Y triple helical domain where substitution of the glycine is usually pathogenic (Butterfield et al. 2013. PubMed ID: 24038877). This variant is interpreted as likely pathogenic. - |
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2297 of the COL6A3 protein (p.Gly2297Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy and clinical features of collagenopathies (PMID: 30564623, 35487415). ClinVar contains an entry for this variant (Variation ID: 287133). 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 COL6A3 protein function with a positive predictive value of 80%. This variant disrupts the triple helix domain of COL6A3. 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 COL6A3, missense variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at