ClinVar Genomic variation as it relates to human health

Variant summary: The SCN5A c.3988G>A (p.Ala1330Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120776 control chromosomes. This variant has been reported in one LQTS family with co-segregation in 5 affected members (Smits_2005). No additional patient who carries this variant has been reported so far. In vitro study showed this variant shifts the voltage range of I(Na, window) activity to more positive potentials. Here the counter-acting effect of outward K+ current is reduced and may delay AP repolarization, explaining the LQT3 phenotype (Smits_2005). However, the magnitude of the electrophysiological findings reported by the authors does not seem dramatically different from those of the wild-type controls as compared to the other pathogenic variant (p.A1330P) which is known to be associated with LQT3. Nevertheless, the authors interpret their findings as an increased persistent inward current caused by this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic until additional functional studies and co-segregation of this variant in other patients/families with LQT3 are obtained.

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that A1330T induces a positive shift in the voltage-dependence of steady-state inactivation and accelerates recovery from inactivation likely resulting in delayed repolarization (Smits et al., 2005).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as likely pathogenic but additional evidence is not available (ClinVar Variant ID# 67842; ClinVar); This variant is associated with the following publications: (PMID: 19841300, 12566525, 17854786, 16039271, 28118183, 29654130, 31317183, 11535573, 30193851, 33087929, 33164571)

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1330 of the SCN5A protein (p.Ala1330Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16039271). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67842). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 16039271). This variant disrupts the p.Ala1330 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11535573). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The c.3988G>A (p.A1330T) alteration is located in exon 23 (coding exon 22) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 3988, causing the alanine (A) at amino acid position 1330 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12566525;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.