Submissions for variant NM_002246.3(KCNK3):c.832A>T (p.Ser278Cys)

gnomAD frequency: 0.00012  dbSNP: rs368524386

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651584	SCV000773438	uncertain significance	Pulmonary hypertension, primary, 4	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 278 of the KCNK3 protein (p.Ser278Cys). This variant is present in population databases (rs368524386, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KCNK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 541325). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNK3 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002531980	SCV003692472	uncertain significance	Inborn genetic diseases	2021-08-12	criteria provided, single submitter	clinical testing	The c.832A>T (p.S278C) alteration is located in exon 2 (coding exon 2) of the KCNK3 gene. This alteration results from a A to T substitution at nucleotide position 832, causing the serine (S) at amino acid position 278 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786148	SCV000924821	uncertain significance	not provided	2017-09-28	no assertion criteria provided	provider interpretation	Found in a previously healthy 16-year-old male who died in his sleep, with a negative autopsy. He had postmortem genetic testing for Arrhythmias, Cardiomyopathies, and Sudden Death in Epilepsy with the Invitae laboratory. Results showed one variant: • p.Ser278Cys (S278C; c.832A>T) in the KCNK3 gene The KCNK3 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant pulmonary arterial hypertension (PMID: 23883380, 24742047). This was not our patient's phenotype. p.Ser278Cys (S278C; c.832A>T) in exon 2 of the KCNK3 gene (NM_002246.2) Chromosome position 2:26951083 A / T Based on the information reviewed below, we classify this as a Variant of Unknown Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a polar Serine with a polar Cysteine capable of forming disulfide bridges. Serine at this location is extremely poorly conserved across ~100 vertebrate species for which we have data. In fact, Cysteine is the default amino acid in at least 12 mammalian species. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". This variant was reported in 37 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 13/12,420 South Asians (for the highest allele frequency: 0.052%), 17/37,446 non-Finnish Europeans (MAF 0.023%), 3 Latinos, 2 “Other”, and 1 Finnish European and 1 African individual. Overall MAF 0.02%. Our patient's ancestry is Caucasian. The phenotype of those individuals 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.