ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with reduction of the potassium current during the cardiac action potential (Eldstorm et al. 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19862833, 12653681, 25525159, 24372464, 19716085, 28438721, 32048431, 31737537, 31565860, 34426522, 31589614, 32096762, 33990467, 20421371, 34135346, 12051962, 34860437, 34505893, 23392653)

Variant summary: KCNQ1 c.604G>A (p.Asp202Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 248246 control chromosomes (gnomAD). c.604G>A has been reported in the literature in the heterozygous state in individuals with QT prolongation or borderline QT prolongation, and in the homozygous and compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome (JLNS) (examples: Wang_2002, Al-Aama_2014, Akgun-Dogan_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant impairs normal function of the protein (Eldstrom_2009). The following publications have been ascertained in the context of this evaluation (PMID: 34860437, 24372464, 20421371, 12051962, 27920829). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 202 of the KCNQ1 protein (p.Asp202Asn). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 20421371). 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. ClinVar contains an entry for this variant (Variation ID: 53077). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 12051962, 19716085, 24372464, 31737537). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199472702, gnomAD 0.003%).

Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PP3

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 3 of the KCNQ1 gene and replaces aspartic acid with asparagine at codon 202 of the KCNQ1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing and computational prediction also suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain S3. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant impairs channel function by accelerating both activation and deactivation kinetics in transfected cells (PMID: 20421371). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID: 19716085, 31737537, 32893267). This variant has also been observed in homozyous and compound heterozygous sate in two individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 12051962, 24372464), indicating that this variant contributes to disease. This variant has been identified in 3/279614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 3 of the KCNQ1 gene and replaces aspartic acid with asparagine at codon 202 of the KCNQ1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing and computational prediction also suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain S3. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant impairs channel function by accelerating both activation and deactivation kinetics in transfected cells (PMID: 20421371). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID: 19716085, 31737537, 32893267). This variant has also been observed in homozyous and compound heterozygous sate in two individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 12051962, 24372464), indicating that this variant contributes to disease. This variant has been identified in 3/279614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The c.604G>A pathogenic mutation (also known as p.D202N), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 604. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the aspartic acid at codon 202 to asparagine, an amino acid with highly similar properties. This alteration has been detected in the heterozygous state in individuals with QT prolongation or borderline QT prolongation, and in the homozygous and compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome (JLNS) (Wang Z et al. Mol Genet Metab. 2002;75:308-16; Al-Aama JY. Clin Genet. 2015;87(1):74-9). In one study, this alteration was reported to result in altered splicing; however, supporting evidence was not provided (Kapplinger J et al. Heart Rhythm. [Abstract #AB22-05] 2016 May;13(5):S1-S608). In functional in vitro analyses, this alteration demonstrated adverse affects on the current amplitude and cardiac action potential of the voltage-gated potassium ion channel (Eldstrom J et al. J Gen Physiol. 2010;135:433-48). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

KCNQ1: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP3

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12051962;PMID:12653681;PMID:19716085;PMID:20421371). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.