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.