ClinVar Genomic variation as it relates to human health

In a 2-year-old boy with second-degree atrioventricular conduction block (PFHB1A; 113900) necessitating a pacemaker, Viswanathan et al. (2003) identified a heterozygous 1535C-T transition in the SCN5A gene, resulting in a thr512-to-ile (T512I) substitution. In addition, there was a homozygous 1673A-G transition, resulting in a his558-to-arg (H558R) substitution. H558R (rs1805124) is a polymorphism present in 20% of the population (Yang et al., 2002). One of the patient's alleles contained both T512I and H558R. The patient's father was heterozygous for the H558R substitution, the asymptomatic mother was compound heterozygous for the T512I and H558R substitutions, and 2 sibs were heterozygous for the H558R substitution. Functional expression studies showed that activation and inactivation of wildtype and H558R channels were similar. By contrast, voltage-dependent activation and inactivation of the T512I channel was shifted negatively by 8 to 9 mV and had enhanced slow activation and slower recovery from inactivation compared to the wildtype channel. Studies of the double H558R/T512I channel showed that H558R eliminated the negative shift induced by T512I, but only partially restored the kinetic abnormalities. Viswanathan et al. (2003) suggested that enhanced slow inactivation disproportionately affected Purkinje cells, which have a longer action potential duration and smaller diastolic interval, resulting in slowed atrioventricular conduction. Darbar et al. (2008) stated that the H558R variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected H558R in 59 patients with lone atrial fibrillation and in 130 patients with atrial fibrillation associated with other heart disease, as well as in 128 of 720 control chromosomes, for a minor allele frequency of approximately 25%. (less)