ClinVar

Description

The ABCC6 c.1171A>G variant is predicted to result in the amino acid substitution p.Arg391Gly. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states, as well as in the presence of other ABCC6 variants (phase not established), in individuals with pseudoxanthoma elasticum (PXE) of variable severity and onset (Chassaing et al. 2004. PubMed ID: 15086542; Misksch et al. 2005. PubMed ID: 16086317; Ringpfeil et al. 2006. PubMed ID: 16410789, Schulz et al. 2006. PubMed ID: 16835894, Pfendner et al. 2007. PubMed ID: 17617515; Legrand et al. 2017. PubMed ID: 28102862; De Vilder et al. 2018. PubMed ID: 29722917; Boraldi et al. 2020. PubMed ID: 32039214; Issa et al. 2020. PubMed ID: 32442430). It has been reported in the heterozygous state in the absence of a second variant in at least one individual from an ischemic stroke cohort (Table S3, De Vilder et al. 2018. PubMed ID: 29722917). It has been reported in the heterozygous state with and without the presence of a second ABCC6 variant (phase not established), in a limited number of individuals with generalized calcification of infancy (GACI) and/or vascular anomalies (Nitschke et al. 2012. PubMed ID: 22209248; Li et al. 2014. PubMed ID: 24008425; Mattassi et al. 2018. PubMed ID: 28655553). A recent study reported this variant along with a second variant in 3 individuals with late onset PXE consisting of only ocular features with an onset of 80 years of age or older (Issa et al. 2020. PubMed ID: 32442430). This variant is thought to be a low penetrance hypomorphic allele capable of resulting in disease when combined with a severe pathogenic variant on the opposite allele (in trans) (Issa et al. 2020. PubMed ID: 32442430). More recently, the penetrance of this variant was hypothesized to be only 2%; however, when penetrant, it manifests a similar disease severity and progression to what two fully penetrant loss of function variants cause (Szeri et al. 2022. PubMed ID: 36317459). In an updated version of gnomAD (v4), this variant has an allele frequency of 0.84% in individuals of Middle Eastern descent, including 57 homozygous individuals globally, which is likely too frequent to be a primary cause of disease. This variant is interpreted as likely pathogenic with incomplete penetrance.