11-2587636-GC-GCC
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000218.3(KCNQ1):c.1201dup(p.Arg401ProfsTer62) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A399A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000218.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1201dup | p.Arg401ProfsTer62 | frameshift_variant | 9/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1201dup | p.Arg401ProfsTer62 | frameshift_variant | 9/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.820dup | p.Arg274ProfsTer62 | frameshift_variant | 9/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.844dup | p.Arg282ProfsTer62 | frameshift_variant | 9/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.661dup | p.Arg221ProfsTer62 | frameshift_variant | 4/11 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251228Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135824
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461596Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727104
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | KCNQ1: PVS1, PM2, PS4:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2023 | Frameshift 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: 22995991, 15840476, 24357532, 17470695, 23631430, 31765965, 34319147, 31737537, 26582918, 24606995, 35647048) - |
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | The c.1201dup (p.Arg401Profs*62) variant in the exon 9 of KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, creates a premature termination codon that is predicted to lead to absent or truncated protein product. This variant has been identified in several individuals (>10) affected with Long QT syndrome (LQTS) (PMID: 15840476, 17470695, 23631430, 24606995, 24357532, 19862833, 19716085, 31765965). Loss of function variants are known to be pathogenic for KCNQ1 gene (PMID: 26669661, 29532034, 23098067). This variant is found to be rare (1/251228; 0.00000398) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 52972). Therefore, the c.1201dup (p.Arg401Profs*62) variant in the KCNQ1 gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg401Profs*62) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52972). This premature translational stop signal has been observed in individuals with long QT syndrome (PMID: 15840476, 17470695, 23631430, 24357532). - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2022 | The c.1201dupC pathogenic mutation, located in coding exon 9 of the KCNQ1 gene, results from a duplication of C at nucleotide position 1201, causing a translational frameshift with a predicted alternate stop codon. This alteration has been reported in multiple individuals with long QT syndrome (Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Moss AJ et al. Circulation. 2007;115(19):2481-9; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17(7):553-61; Torekov SS et al. Diabetes. 2014;63(4):1315-25). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 22, 2023 | This variant (also known as P400fs*62 in the literature) inserts 1 nucleotide in exon 9 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with or suspected of long QT syndrome (PMID: 15840476, 17470695, 23631430, 24357532, 24606995, 31765965). This variant has been identified in 1/251228 chromosomes 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