rs397508075
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000218.3(KCNQ1):c.1075C>T(p.Gln359*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,716 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000218.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ1 | ENST00000155840.12 | c.1075C>T | p.Gln359* | stop_gained | Exon 8 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
| KCNQ1 | ENST00000335475.6 | c.694C>T | p.Gln232* | stop_gained | Exon 8 of 16 | 1 | ENSP00000334497.5 | |||
| KCNQ1 | ENST00000496887.7 | c.771+1709C>T | intron_variant | Intron 8 of 15 | 5 | ENSP00000434560.2 | ||||
| KCNQ1 | ENST00000646564.2 | c.588+1709C>T | intron_variant | Intron 3 of 10 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461716Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727168
GnomAD4 genome
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:3
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome 2 (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome 1 (LQTS, MIM#192500), familial atrial fibrillation 3 (MIM#607554) as well as Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterised by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic, and reported in individuals with long QT syndrome (ClinVar, PMID: 19841300). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with long QT syndrome, and as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar, PMIDs: 19841300, 21956039, 25294783). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:3
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22956155, 25294783, 21956039, 26370830, 19841300, 29265593, 19716085, 34505893) -
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.Gln359Stop We classify this variant as likely disease-causing. This nonsense variant has been reported previously in 4 unrelated patients tested for LQTS through the Familion laboratory (Kapplinger et al. 2009). It is also described by Vijayakumar et al. (2014) in a female patient with a QTc of 516 and an ICD (unknown if this patient or a family member was tested at Familion). No segregation analysis is available. Kapplinger et al. report that it was absent from 1300 control individuals (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). This specific variant is not present in the NHLBI ESP. It is predicted to cause loss of normal protein function either due to a prematurely truncated protein or absent protein product due to nonsense mediated mRNA decay. Other nonsense mutations in the KCNQ1 gene have been reported in HGMD in association with LQTS. -
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Long QT syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Gln359*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 19716085, 19841300, 22956155). ClinVar contains an entry for this variant (Variation ID: 52950). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: KCNQ1 c.1075C>T (p.Gln359X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 254048 control chromosomes. c.1075C>T has been reported in the literature in individuals affected with Long QT Syndrome (example, Kapplinger_2009, Kapa_2009, Ware_2013, Lieve_2013, Burns_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The c.1075C>T (p.Gln359*) variant in the KCNQ1 gene is expected to introduce a premature translation stop codon resulting in an absent or disrupted protein. This variant has been reported in multiple individuals with long QT syndrome (PMID: 19716085, 19841300, 22956155, 23631430, 27920829, 21956039, 25294783). Loss of function is a known mechanism of disease for LongQT syndrome. Clinvar contains an entry for this variant (Variation ID: 52950). This variant is absent in the general population database (gnomAD). Based on the available evidence c.1075C>T (p.Gln359*) in the KCNQ1 gene is classified as pathogenic. -
Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
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KCNQ1-related disorder Pathogenic:1
The KCNQ1 c.1075C>T variant is predicted to result in premature protein termination (p.Gln359*). This variant was reported in multiple individuals with long QT syndrome (Kapplinger et al. 2009. PubMed ID: 19716085; Schwartz et al. 2021. PubMed ID: 34505893, supplementary data). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.Q359* pathogenic mutation (also known as c.1075C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1075. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been reported in individuals with long QT syndrome (LQTS) (Kapa S et al. Circulation, 2009 Nov;120:1752-60; Vijayakumar R et al. Circulation, 2014 Nov;130:1936-43). Additionally, this alteration was detected in a pediatric LQTS cohort and in a study of LQTS clinical genetic testing (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Aziz PF et al. Circ Arrhythm Electrophysiol, 2011 Dec;4:867-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Cardiac arrhythmia Pathogenic:1
This variant changes 1 nucleotide in exon 8 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with long QT syndrome (PMID: PMID: 19716085, 19841300, 22956155). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at