ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.740T>A (p.Leu247His) (rs199472767)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045965 SCV000073978 uncertain significance Long QT syndrome 2019-10-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 374 of the KCNQ1 protein (p.Leu374His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 15840476, Invitae). ClinVar contains an entry for this variant (Variation ID: 52961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000721103 SCV000234478 uncertain significance not provided 2017-08-08 criteria provided, single submitter clinical testing The L374H variant of uncertain significance in the KCNQ1 gene has been reported previously in at least one individual who underwent LQTS genetic testing; however, detailed clinical information and segregation data were not provided (Tester et al., 2005; Kapplinger et al., 2009). This variant has also been identified both independently and in conjunction with additional cardiogenetic variants in several individuals referred for LQTS genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The L374H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L374H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Located in the C-terminus of KCNQ1, variants in nearby residues (A372D, S373P, W379G, W379S) have also been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014); however, the clinical significance of these variants has not been definitively determined.
Ambry Genetics RCV000618916 SCV000737968 pathogenic Cardiovascular phenotype 2020-07-15 criteria provided, single submitter clinical testing The p.L374H pathogenic mutation (also known as c.1121T>A), located in coding exon 8 of the KCNQ1 gene, results from a T to A substitution at nucleotide position 1121. The leucine at codon 374 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in more than ten individuals with prolonged QT intervals and other phenotypes consistent with long QT syndrome and has been shown to segregate with disease in one family (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Hammami Bomholtz S et al. Pacing Clin Electrophysiol, 2020 02;43:210-216; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). Functional studies suggest that this alteration altered ion channel function (Hammami Bomholtz S et al. Pacing Clin Electrophysiol, 2020 02;43:210-216). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV001181320 SCV001346441 likely pathogenic Arrhythmia 2021-02-10 criteria provided, single submitter clinical testing This missense variant replaces leucine with histidine at codon 374 in the C-terminal cytoplasmic domain of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes retention of the channels in the endoplasmic reticulum and complete loss of potassium current (PMID: 31899541). This variant has been reported in at least seven unrelated individuals affected with long QT syndrome and six referred for long QT syndrome genetic testing (PMID: 15840476, 19716085, 31899541). It has also been shown that this variant segregates with long QT syndrome in six individuals from a family (PMID: 31899541). This variant has been identified in 1/251078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000721103 SCV001713556 uncertain significance not provided 2019-10-21 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057558 SCV000089077 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:15840476;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000721103 SCV000280141 likely pathogenic not provided 2016-04-20 no assertion criteria provided provider interpretation p.Leu374His (L374H; c.1121T>A) in exon 8 of the KCNQ1 gene (NM_000218.2) We care for another LQTS family in which it segregates extensively with disease. Based on the information reviewed below, we classify it as Likely Disease Causing, concluding that there is sufficient evidence for its pathogenicity to warrant using it for diagnosis and for predictive genetic testing in at-risk family members. This variant has previously been reported in two unrelated individuals tested for LQTS (Tester et al. 2005; Kapplinger et al. 2009), with no published segregation data. However, we have seen it segregate in 6 affected members of a family with LQTS, across 5 meioses, which would happen by chance in only 3% (1/32) of cases. (Additionally, it was absent from two family members who showed no LQTS phenotype.) Per personal communication, there are also 11 cases at genetic testing labs. In the literature: Kapplinger et al. (2009) identified the Leu374His variant in one individual undergoing clinical genetic testing for LQTS. This individual was among the first 2500 people referred for clinical long QT genetic testing at Familion laboratory. Of note, there is no phenotypic data available for this cohort. The low variant yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen along with another variant (9% of the cohort had multiple variants), complicate analysis. Tester et al. (2005) identified it in a patient referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS testing. Leu374His results in a non-conservative amino acid substitution of a non-polar Leucine with a positively charged Histidine at a residue that is conserved across species. Variation at nearby residues +/- 10 has been associated with LQTS, which may support the functional importance of this region of the protein: Asn365His, Arg366Gln, Arg366Pro, Arg366Trp, Gln367His, Ala371Thr, Ala372Asp, Ser373Pro, Trp379Arg, Trp379Gly, Trp379Ser, Arg380Gly, Arg380Ser, (HGMD professional version as of January 17, 2014). According to the Invitae report, Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant may cause disease. However, when Kapa et al. (2009) compared 388 "clinically definite" LQTS probands to ~1300 healthy controls, they found that while controls do have variants in all regions of the protein, LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). p.Leu374His is in the cytoplasmic domain of the protein, in which missense variants are 22x more frequent in LQTS cases than in controls (Kapa et al. 2009). In total the variant has not been seen in >60,000 published controls and individuals from publicly available population datasets. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 4/20/2016. Variation at this codon has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). The 5778 "Latino" individuals are mostly Mexican. Our patient's ancestry is Caucasian and Mexican. These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. The variant was also not observed in published controls: 1300 ostensibly healthy volunteers (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other; Kaplinger et al. 2009); 744 individuals from 4 ethnic groups (Tester et al. 2005).

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