|Mutation (gDNA level)||chr2-238289767-T-C|
|Mutation (cDNA level)||c.1688A>G|
|Prediction at protein level||D563G (p.Asp563Gly)|
|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|
|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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Interesting that this mutation may not effect the production of collagen. We have three generations (possible four generations) with this mutation and do have symptoms of Bethlem Myopathy.
Dear Dr York,
many thanks for your appreciated comment! Our a priori interpretation is substantially based on allele frequency values. The allele frequency reported in the ExAC database (0.0023 or, if you prefer, 0.23%) has been calculated on a total of 121,374 alleles among Africans, Europeans, Americans, Asians and other ethnicities and we therefore deem it as quite reliable. Bethlem myopathy is mainly autosomal dominant and I assume that also the family you are describing shows a typical autosomal dominant pattern of transmission. If the D563G mutation would be causative for autosomal dominant Bethlem myopathy, the prevalence of the disease (caused only by this mutation!) would be about 1 patient every 500 inhabitants! But even in case of autosomal recessive transmission, the frequency of this variant does not appear to be compatible with the estimated prevalence of autosomal recessive Bethlem and Ullrich congenital myopathy. The D563G is currently reported in the ClinVar database with an uncertain significance, with hints that it might be a rare benign variant in the population of European ancestry. Most in silico analyses infer this amino acid change to be possibly damaging, but we all know that in silico predictions must be taken very carefully.
Of note, this mutation is reported also in the LOVD database (http://www.dmd.nl/nmdb2/variants.php?select_db=COL6A3&action=search_all&search_Variant%2FDNA=c.1688A>G), where it is described in both the unaffected parent and the affected child, with the child also carrying a variant in COL6A1.
It should be mentioned that, especially if the pedigree contains a not huge number of affected individuals, chances remains that the segregation of a certain variant with the disorder is fortuitous (this has already been observed in the past in polycystic kidney disease families with patients affected accross multiple generations)
For the above reasons, we believe that there is a given likelihood that the D563G is not affecting protein function. The last word remains of course to the referring physician/geneticist, who has the wider picture on the family and on all sequencing data.
If you want, we remain available to see the pedigree of the clinical case you are referring to.