Tentatively classified as benign. Initially reported as a recessive cause of infantile arterial calcification, but with no statistical significance. Other variants have been implicated as causal in these cases this variant. 5% allele frequency in caucasians contradicts this variant as having any highly pathogenic effect.
dbSNP reports that this variant has 5% allele frequency in a low-coverage CEU panel (6/120 chromosomes, from 1000 genomes) and 2.6% in a mixed panel of Caucasian & African American samples (2/78 chromosomes). Lorenz-Depiereux et al. point to this as suggesting that the variant is a not causal.
The predicted incidence of homozygotes (1 in 400) vs. the incidence of the disease (quite rare) implies that this variant cannot have a high penetrance pathogenic effect. There is no statistically significant higher incidence of this variant in Rutsch et al’s findings when compared to combined dbSNP numbers. In addition, all reported cases with this variant now have other causal variants implicated. For this reason, we mark the variant as benign.
In a study of 11 idiopathic cases of infantile arterial calcification, this variant was reported homozygously in one case and heterozygously in combination with L579F (in cis) and a frameshift (in trans) in another. Counting alleles, this is a case+: 3, case-: 19. If we use the combined data from dbSNP, control+: 8, control-: 190. This has p=0.08.
The footnote to Table 3 states: “The mutation reported in this paper (c.2320C>T [p.Arg774Cys]) has since been shown to be a polymorphism (rs28933977) with a minor allele frequency of 5%.”
These authors follow up on the homozygous case from Rutsch et al, a Turkish family, and find the patient is also homozygous for E266V. The father is homozygous for the E266V variant as well but has a later onset phenotype, developing an aortic root dissection at the age of 28 yrs.