ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.223G>A (p.Asp75Asn) (rs199472702)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182091 SCV000234394 likely pathogenic not provided 2020-12-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect with reduction of the potassium current during the cardiac action potential (Eldstorm et al. 2010); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 53077; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31565860, 31737537, 32048431, 23392653, 12051962, 28438721, 19716085, 19862833, 24372464, 25525159, 12653681, 20421371)
Ambry Genetics RCV000620936 SCV000738155 pathogenic Cardiovascular phenotype 2019-02-27 criteria provided, single submitter clinical testing 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.
Invitae RCV001379267 SCV001577038 likely pathogenic Long QT syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 202 of the KCNQ1 protein (p.Asp202Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 3 of the KCNQ1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is present in population databases (rs199472702, ExAC 0.009%). This variant has been reported in the homozygous state and as a compound heterozygous in individuals with Jervell and Lange-Nielsen syndrome (PMID: 24372464, 12051962), and in an individual refered for long QT testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 53077). Experimental studies have shown that this missense change affected activation and deactivation of the potassium channel (PMID: 20421371). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057718 SCV000089237 not provided Congenital long QT syndrome no assertion provided literature only 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.

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