ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.580G>C (p.Ala194Pro) (rs199472699)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057712 SCV000089231 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:10973849). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Integrated Genetics/Laboratory Corporation of America RCV000223826 SCV000695993 uncertain significance not provided 2016-04-05 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.580G>C variant affects a conserved nucleotide, resulting in amino acid change from Ala to Pro. 4/4 in-silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant has been reported in at least 3 patients with LQTS and was not found in 120200 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic without evidence to independently evaluate. Taken together, this variant was classified as VUS-possibly pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223826 SCV000280159 likely pathogenic not provided 2014-10-13 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ala194Pro This variant has been reported in two unrelated individuals with long QT syndrome. Splawski et al (2000) identified the variant in one individual with long QT syndrome. Kotta et al (2010) genotyped families of Greek descent with long QT syndrome and identified the variant in one infant with a QTc of 480 ms. While the two publications both include European long QT samples, Kotta et al (2010) specifically state that there is no published data on the Greek long QT population therefore it is likely that these are two separate and unrelated probands with long QT and this variant. Neither publication included segregation data. This is a conservative amino acid change with a nonpolar Alanine replaced with a nonpolar Proline at codon 194. The Alanine at codon 194 is completely conserved as are neighboring residues. In silico analysis with PolyPhen2 predicts the variant to be probably damaging. Variants in nearby codons have been associated with long QT syndrome (p.Arg192Pro, p.Arg195Trp, p.Ile198Val) (, Kapplinger et al 2009, Napolitano 2005). The variant is in the intracellular linker between the S2 and S3 transmembrane domains (Kapplinger et al 2009). This region of the channel is particularly enriched with pathogenic variants. Variants in this region and elsewhere in the transmembrane domains have been reported as an independent risk factor for clinical severity (Moss et al 2007). We were unable to find in vitro data on the functional impact of the variant. Pan et al (2009) note in the introduction to their manuscript that this variant has been shown to reduce IK currents, however they do not provide the primary reference. Kotta et al (2010) did not observe the variant in 100 control individuals of Greek descent. Splawski et al (2000) did not find variant in 200 control individuals. Thus in total this variant has not been seen in 300 published controls. Based on these data it seems likely, though not definite, that this variant causes long QT syndrome.

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