| Gene | COL6A3 |
| Mutation (gDNA level) | chr2-238289767-T-C |
| Mutation (cDNA level) | c.1688A>G |
| Reference sequence | NM_004369.3 |
| Prediction at protein level | D563G (p.Asp563Gly) |
| Mutation type | missense |
| Exon/intron location | exon 5 of 44 |
| Amino acid location | aa 563 of 3178 |
| Gene associated phenotype(s) | Bethlem myopathy 1; Dystonia 27; Ullrich congenital muscular dystrophy 1 |
| ClinVar ID | 94910 |
| dbSNP ID | rs112913396 |
| Clinical information | n.a. |
| A priori interpretation | possibly not affecting function |
| Notes | Single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical domain of any of the three COL6A genes constitute the most frequent pathogenic mechanism in these genes. Given the high number of mutations that result in benign amino acid changes described for the three COL6A genes, it is difficult to be sure about the pathogenicity of missense mutations other than glycine substitutions within the triple helical domain. The highest allele frequency reported for this mutation is 0,23% (ExAC), which would lead to an estimated disease prevalence of 1:189,000 for autosomal recessively inherited Ullrich congenital muscular dystrophy caused only by this mutation in the COL6A3 gene. Although the disorder is probably underdiagnosed, the current estimated prevalence of Ullrich congenital muscular dystrophy, caused by any mutation in any of the three COL6A genes, is around 1:770,000. Autosomal recessive instances of Bethlem myopathy have been reported, but are thought to be rare. Because of these considerations on allele frequency and given that the missense change is not affecting a Gly residue, there is given likelyhood that this variant is not affecting the protein function. Careful genotype-phenotype correlation and familial studies must be carried out to gather further evidence. In regard to the recently characterized dystonia 27, no disease prevalence is available yet. Evidence reported thus far indicates that mutations causing dystonia 27 are loss-of-function mutations and that all affected individuals have at least one pathogenic allele in exon 41. |
| References | PMID 20301676, PMID 25533456 , PMID: 26004199 |
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