NM_004369.4:c.7447A>G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBS1_Supporting
The NM_004369.4(COL6A3):c.7447A>G(p.Lys2483Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000717 in 1,614,090 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004369.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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COL6A3 | NM_004369.4 | c.7447A>G | p.Lys2483Glu | missense_variant | Exon 36 of 44 | ENST00000295550.9 | NP_004360.2 | |
COL6A3 | NM_057167.4 | c.6829A>G | p.Lys2277Glu | missense_variant | Exon 35 of 43 | NP_476508.2 | ||
COL6A3 | NM_057166.5 | c.5626A>G | p.Lys1876Glu | missense_variant | Exon 33 of 41 | NP_476507.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000612 AC: 154AN: 251446Hom.: 1 AF XY: 0.000677 AC XY: 92AN XY: 135896
GnomAD4 exome AF: 0.000737 AC: 1077AN: 1461892Hom.: 1 Cov.: 34 AF XY: 0.000737 AC XY: 536AN XY: 727246
GnomAD4 genome AF: 0.000532 AC: 81AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:6Uncertain:2
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Reported previously in the compound heterozygous state and in the homozygous state in patients with Bethlem myopathy, hyperCKemia, and Type 1 fiber predominance on muscle biopsy. One patient who was homozygous for this variant also harbored a pathogenic variant in a separate gene; however, segregation studies could not be completed (PMID: 30706156, 32403337, 38155714); Reported previously in patients with with suspected limb girdle muscular dystrophy (PMID: 34720847, 30564623); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 30706156, 34720847, 37526466, 38127101, 38155714, 36964972, 33441455, 37273706) -
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Bethlem myopathy 1A Pathogenic:3
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This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2483 of the COL6A3 protein (p.Lys2483Glu). This variant is present in population databases (rs139260335, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive COL6A3-related conditions (PMID: 20976770, 26247046, 28688748, 29970176, 32403337, 32448721, 32528171, 33596003, 33749658; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 196977). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL6A3 protein function. For these reasons, this variant has been classified as Pathogenic. -
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COL6A3-related disorder Pathogenic:3
The COL6A3 c.7447A>G variant is predicted to result in the amino acid substitution p.Lys2483Glu. This variant has been reported the homozygous and compound heterozygous states in multiple individuals with COL6A3-related myopathies (see for example, Panadés-de Oliveira et al. 2019. PubMed ID: 30706156; Villar-Quiles et al. 2021. PubMed ID: 33749658; Zídková et al. 2023. PubMed ID: 37526466) and has also been shown to co-segregate with disease in multiple families (Hunter et al. 2015. PubMed ID: 26247046; Stavusis et al. 2020. PubMed ID: 32448721; Mihaylova et al. 2021. PubMed ID: 33596003; Villar-Quiles et al. 2021. PubMed ID: 33749658). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic for autosomal recessive COL6A3-related myopathies. -
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Dystonia 27 Pathogenic:1
This sequence variant is a single nucleotide substitution (A>G) at coding nucleotide 7447 in the COL6A3 gene which results in a lysine to glutamic acid amino acid change at residue 2483 in the COL6A3 protein. This is a previously reported variant (ClinVar) which has been observed in homozygous or compound heterozygous state in several individuals with neuromuscular disorders (PMID: 20976770, 32528171, 32448721, 32403337, 29970176, 28688748, 26247046); in most homozygous cases, the neuromuscular disorders were described as mild with preserved ambulation. This variant is present in 170/282838 alleles (0.06011%), including 1 homozygote, in the gnomAD control population dataset. Structural alysis suggests that this amino acid change will alter the ability of COL6A3 protein to interact with binding targets (PMID: 32448721). Multiple bioinformatic tools predict that this amino acid change will be damaging, and the Lys2483 residue is highly conserved in vertebrates. Functiol studies assessing the effect of this variant on protein structure or activity have not been performed, to our knowledge. Based on the available evidence, we consider this variant to be likely pathogenic. ACMG Criteria: BP1, PM3, PP3, PS4 -
Ullrich congenital muscular dystrophy 1A Pathogenic:1
Variant summary: COL6A3 c.7447A>G (p.Lys2483Glu) results in a conservative amino acid change located in the von Willebrand factor, type A repeat domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251446 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.7447A>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Limb-girdle muscular dystrophy, and in several cases other causes were ruled out by whole exome sequencing (e.g., Brinas_2010, Hunter_2015, Sframeli_2017, Nallamilli_2018, Fichna_2018, Villar-Quiles_2021, and internal LCA cases). Affected individuals with variant of interest display a relatively mild phenotype (e.g., Bethlem myopathy), often with proximal muscle weakness, skin abnormalities, and joint contractures, however affected individuals do not seem to experience complete loss of ambulation (Villar-Quiles_2021). Individuals who are homozygous for this variant exhibit different clinical features to those who are compound heterozygous, and some do not have typical COL6-related myopathy phenotypes, while all tested parents were healthy heterozygous carriers (Villar-Quiles_2021). The relatively high allele frequency, including an observed homozygous individual in the control population, as well as the different phenotypes observed in the homozygous patients, lead some authors to suggest that this variant may act as a modulator of the clinical phenotype, and recommend using an in-depth analysis of clinical features and ancillary tests in order to interpret the genetic analysis regarding this variant (Villar-Quiles_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, although reduced- or normal collagen VI secretion in fibroblasts derived from a subset of homozygous patients was noted (Villar-Quiles_2021). The following publications have been ascertained in the context of this evaluation (PMID: 20976770, 29970176, 26247046, 35239206, 30564623, 28688748, 33749658). ClinVar contains an entry for this variant (Variation ID: 196977). To our knowledge, this variant has not been reported in patients with autosomal dominant myopathy. Based on the evidence outlined above, the variant seems to be associated with milder myopathic phenotypes in biallelic patients, therefore it was classified as likely pathogenic. -
Bethlem myopathy 1C Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at