ClinVar Genomic variation as it relates to human health

This missense variant replaces valine with isoleucine at codon 1340 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant markedly reduces sodium currents in vitro (PMID: 19648062). This variant has been reported in four individuals affected with and in one individual suspected of having Brugada syndrome (PMID: 19648062, 20129283, 20609320, 30662450, 32268277), in four unaffected relatives from one of the affected families (PMID: 20609320), and in two individuals with borderline ECG alternations (PMID: 34428338). This variant has also been identified in 13/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1340 of the SCN5A protein (p.Val1340Ile). This variant is present in population databases (rs199473605, gnomAD 0.04%). This missense change has been observed in individuals with Brugada syndrome (PMID: 19648062, 20129283, 20609320, 30662450; Invitae). ClinVar contains an entry for this variant (Variation ID: 67849). 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: 19648062). For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces valine with isoleucine at codon 1340 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant markedly reduces sodium currents in vitro (PMID: 19648062). This variant has been reported in four individuals affected with and in one individual suspected of having Brugada syndrome (PMID: 19648062, 20129283, 20609320, 30662450, 32268277), in four unaffected relatives from one of the affected families (PMID: 20609320), and in two individuals with borderline ECG alternations (PMID: 34428338). This variant has also been identified in 13/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The c.4018G>A (p.V1340I) 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 4018, causing the valine (V) at amino acid position 1340 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Variant summary: SCN5A c.4018G>A (p.Val1340Ile) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251416 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05). c.4018G>A has been reported in the literature in individuals affected with Brugada syndrome, complicated conditions of hyperthyroidism, and unspecified individuals from cohorts of Brugada syndrome/general control populations (example, Kapplinger_2010, Walsh_2014, Xu_2023, Yang_2022, Jain_2018, Denham_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished sodium currents compared to the WT SCN5A in HEK-293 cells (Samani_2009). The following publications have been ascertained in the context of this evaluation (PMID: 30662450, 34621001, 30203441, 29557500, 20129283, 33131149, 19648062, 24136861, 37508981, 36129056). ClinVar contains an entry for this variant (Variation ID: 67849). Based on the evidence outlined above, the variant was classified as uncertain significance.

Reported in association with Brugada syndrome; however, this variant was also reported in multiple unaffected family members (Samani et al., 2009; Kapplinger et al., 2010; Garcia-Castro et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies suggest the presence of this variant may alter protein interactions under various experimental conditions; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (Samani et al., 2009); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#67849; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25925977, 32268277, 19648062, 24136861, 20129283, 26633542, 25608792, 25904541, 25163546, 20609320, 22643347, 29557500, 30662450, 22581653, 33131149)

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19648062;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.