ClinVar Genomic variation as it relates to human health

The Arg948His mutation in the KCNH2 gene has been published previously in a single individual from a cohort of Japanese patients with LQTS, and was not detected in 400 control alleles from the same population. Other amino acid substitutions affecting the same codon (Arg948Ser, Arg948Cys) and nearby codons (Ser937Asn, Leu955Val) have also been reported in association with LQTS, further supporting the functional importance of this position and this region of the protein. In addition, Arg948His was not detected in 308 control alleles from individuals of various ethnic backgrounds tested at GeneDx, indicating it is not a common benign variant in these populations. In summary, the presence of Arg948His in the KCNH2 gene is consistent with a diagnosis of LQTS. The variant is found in LQT panel(s).

Variant summary: KCNH2 c.2843G>A (p.Arg948His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 165946 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2843G>A has been reported in the literature in individuals/families affected with Long QT Syndrome (e.g. Itoh_2010, Itoh_2016, Pottinger_2020), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

A Heterozygous Missense variant c.2843G>A in Exon 12 of the KCNH2 gene that results in the amino acid substitution p.Arg948His was identified. The observed variant has a maximum allele frequency of 0.00004/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen- 2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as (Pathogenic/Likely pathogenic/Uncertain significance) Conflicting Interpretations [Variation ID: 67443]. The observed variation has been previously reported in patients affected with long QT syndrome (Itoh H et.al., 2016). For these reasons, this variant has been classified as Likely Pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 948 of the KCNH2 protein (p.Arg948His). This variant is present in population databases (rs199473011, gnomAD 0.02%). This missense change has been observed in individual(s) with prolonged QT (PMID: 20541041, 32009526, 34319147). ClinVar contains an entry for this variant (Variation ID: 67443). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

This missense variant replaces arginine with histidine at codon 948 of the KCNH2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with long QT syndrome (PMID: 20541041, 26669661, 34319147, ClinVar SCV000680268.1) and in an individual with prolonged QTc interval (PMID: 32009526). This variant has been identified in 8/197252 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 missense variant replaces arginine with histidine at codon 948 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 20541041, 26669661) and in an individual with prolonged QTc interval (Pottinger et. al, 2019). This variant has also been identified in 8/197252 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.2843G>A (p.R948H) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 2843, causing the arginine (R) at amino acid position 948 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

KCNH2: PS4:Moderate, PP2

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:20541041). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.