ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1364 of the ALPK3 protein (p.Gly1364Ala). This variant is present in population databases (rs752749949, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666, 32480058). ClinVar contains an entry for this variant (Variation ID: 1284767). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.G1364A variant (also known as c.4091G>C), located in coding exon 6 of the ALPK3 gene, results from a G to C substitution at nucleotide position 4091. The glycine at codon 1364 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a subject with arrhythmogenic right ventricular cardiomyopathy and co-occurred with an ALPK3 frameshift mutation in an adult with hypertrophic cardiomyopathy (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Herkert JC et al. Am Heart J. 2020 Jul;225:108-119). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The p.Gly1364Ala variant has been previously reported in the compound heterozygous statewith a truncating variant (p.Asn1666Thrfs*14) in an adult with hypertrophic cardiomyopathy (Herkert et al., 2020). Additionally, this variant has been reported in the heterozygous state in an individual with arrhythmogenic right ventricular cardiomyopathy with no second variant identified (van Lint et al., 2019).This variant has been identified in 14/124,846 European non-Finnish chromosomes (18/274,450 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency.Computational tools predict that the p.Gly1364Ala is deleterious; however, the accuracy of in silicoalgorithms is limited.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly1364Alavariant is uncertain. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: PM2; PM3_Supporting; PP3]

Has been reported as a variant of uncertain significance in an individual with ARVC (PMID: 30847666); Has been reported as c.4091 G>C in a male with LVH, who also harbored a c.4997delA likely pathogenic variant in the ALPK3 gene (PMID: 32480058); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.4091G>C; p.(G1364A); This variant is associated with the following publications: (PMID: 33076350, 30847666, 32480058)