11-2585300-T-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.1121T>A(p.Leu374His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L374F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1121T>A | p.Leu374His | missense_variant | 8/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1121T>A | p.Leu374His | missense_variant | 8/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.740T>A | p.Leu247His | missense_variant | 8/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.771+1755T>A | intron_variant | 5 | |||||
KCNQ1 | ENST00000646564.2 | c.588+1755T>A | intron_variant |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251078Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135782
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461374Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727014
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 22, 2024 | PP1_strong, PP3, PS3_mod, PS4_strong - |
Likely pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 20, 2016 | 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 (Lati - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro functional studies suggest this variant may damage channel function; however, additional studies are needed to validate the effect of this variant (PMID: 31899541); 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: 19716085, 22581653, 30669290, 28569743, 30937429, 26659599, 15840476, 38255832, 31899541) - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 10, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 374 of the KCNQ1 protein (p.Leu374His). This variant is present in population databases (rs199472767, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 31899541; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52961). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 31899541). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2023 | 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 02, 2023 | This missense variant replaces leucine with histidine at codon 374 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a. 349-391) in the C-terminal cytoplasmic domain. Rare non-truncating 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 causes retention of the channels in the endoplasmic reticulum and complete loss of potassium current (PMID: 31899541). This variant has been reported in over ten unrelated individuals affected with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 15840476, 19716085, 31899541, ClinVar SCV000737968.4, SCV000073978.8, SCV000280141.2, SCV000234478.14). 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 Pathogenic. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at