ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.820A>G (p.Ile274Val) (rs199472728)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182121 SCV000234424 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNQ1 gene. The I274V variant has been reported in association with sudden infant death syndrome (SIDS) and with LQTS (Arnestad et al., 2007; Moss et al., 2007; Kapplinger et al., 2009). However, this variant is observed in 16/25754 (0.06%) alleles from individuals of European (Finnish) ancestry, including one homozygous individual, and in 30/126372 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts, indicating it may be a rare variant in these populations (Lek et al., 2016). The I274V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, functional studies suggest the presence of the I274V variant may alter protein interactions under various experimental conditions; however, it is not known whether these findings are biological or clinically relevant in vivo (Rhodes et al., 2008).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000219577 SCV000271879 uncertain significance not specified 2020-04-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ile274Val variant in KCNQ1 has been reported in the heterozygous state in 1 individual with hearing loss where another variant was not identified on the second copy of the KCNQ1 gene, in at least 1 individual with a prolonged QT interval, and 1 individual with sudden infant death syndrome (Moss 2007, Arnestad 2007, Kapplinger 2009, Amin 2012, Goldenberg 2011, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 67109) and has been identified in 0.02% (30/126372) of European chromosomes and 0.06% (16/25754) of Finnish chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org/). An in vitro patch-clamp study, in which p.Ile274Val was expressed in cultured mammalian cells, suggested that the variant may impact protein function (Rhodes 2008); ; however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Ile274Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ile274Val variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_Supporting.
Invitae RCV001080930 SCV000555810 likely benign Long QT syndrome 2020-11-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000777741 SCV000913702 uncertain significance Arrhythmia 2020-02-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001102797 SCV001259487 uncertain significance Long QT syndrome 1 2017-12-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001108024 SCV001265218 benign Short QT syndrome 2 2017-12-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001108025 SCV001265219 uncertain significance Atrial fibrillation, familial, 3 2017-12-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001108026 SCV001265220 uncertain significance Jervell and Lange-Nielsen syndrome 1 2017-12-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057771 SCV000089290 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:17210839;PMID:19716085;PMID:17999538;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148546 SCV000190259 likely pathogenic SUDDEN INFANT DEATH SYNDROME 2014-06-01 no assertion criteria provided research

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