Submissions for variant NM_002234.4(KCNA5):c.544G>A (p.Gly182Arg)

gnomAD frequency: 0.00008  dbSNP: rs755408841

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001087399	SCV000646994	likely benign	Atrial fibrillation, familial, 7	2024-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000786331	SCV001985417	uncertain significance	not provided	2020-01-13	criteria provided, single submitter	clinical testing	Reported in association with idiopathic pulmonary hypertension; patient-specific clinical data and segregation data were not provided (Remillard et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In vitro functional studies suggest that G182R may affect the KCNA5 channel function (Burg et al., 2010); however, it is not clear how well these studies reproduce in vivo condition; This variant is associated with the following publications: (PMID: 20018952, 17267549, 28341588)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001087399	SCV002049609	uncertain significance	Atrial fibrillation, familial, 7	2020-11-05	criteria provided, single submitter	clinical testing	The KCNA5 c.544G>A; p.Gly182Arg variant (rs755408841) is reported in the literature in an individual affected with pulmonary arterial hypertension (Burg 2010). This variant is found in the Latino population with an overall allele frequency of 0.11% (40/35432 alleles in the Genome Aggregation Database. The glycine at codon 182 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.924). Functional studies suggest that the variant protein forms functional channels when expressed in cultured cells, but it exhibits reduced processing and altered inactivation kinetics (Burg 2010). Although the population frequency of this variant appears inconsistent with disease, due to conflicting information, the clinical significance of the p.Gly182Arg variant is uncertain at this time. References: Burg ED et al. Tetramerization domain mutations in KCNA5 affect channel kinetics and cause abnormal trafficking patterns. Am J Physiol Cell Physiol. 2010 Mar;298(3):C496-509.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786331	SCV000925106	uncertain significance	not provided	2018-01-24	no assertion criteria provided	provider interpretation	p.Gly182Arg (G182R; c.544G>A) in exon 1 of the KCNA5 gene (NM_002234.3; ENST00000252321.4) Chromosome position: 12:5153857 G / A Found in a male patient with early-onset lone atrial fibrillation. The KCNA5 gene has been associated with familial atrial fibrillation. Based on the information reviewed below, including its relatively high frequency among individuals with Latino ancestry like our patient, we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has previously been reported in two individuals with idiopathic pulmonary hypertension both taking part in the same study (Remillard et al. 2007; PMID: 17267549), and one with Brugada syndrome (Proost et al. 2017). There is no informative segregation information. Of note, 12% of the participants in the Remillard study were Hispanic. The researchers reported that this missense change affects KCNA5 channel inactivation and localization in vitro (Burg et al. 2010; PMID: 20018952), although it does form functional channels. According to these authors, the variant is located in the highly conserved NH2-terminal tetramerization domain (T1) of KV channels which is important for proper channel assembly, association with regulatory subunits, and localization of the channel to the plasma membrane. They note that the glycine at position 182 is 100% identical in the T1 domains of all 17 human KCNA (KV1), KV2 (KCNB), KV3 (KCNC), and KV4 (KCND) subunits examined (KCNA1–7, KCNA10, KCNB1–2, KCNC1–4, and KCND1–3). This is a distinctly nonconservative amino acid change, resulting in the replacement of a nonpolar Glycine with a positively-charge Arginine with a much larger side-chain. Glycine at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also very highly conserved. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. This variant was reported in 54 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 41 Latinos (for the highest allele frequency: 0.12%), 3 East Asians, 8 non-Finnish Europeans, 1 African, and 1 “Other” ancestry individual. It is present at a higher frequency than would be expected for a pathogenic variant, and is particularly prevalent among individuals with our patient’s Latino ancestry—which suggests that it might be a benign ethnicity-specific variant. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.