rs397508112
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000218.3(KCNQ1):βc.488delβ(p.Leu163ArgfsTer74) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000548 in 1,460,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
KCNQ1
NM_000218.3 frameshift
NM_000218.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.81
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 11-2570637-CT-C is Pathogenic according to our data. Variant chr11-2570637-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570637-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.488del | p.Leu163ArgfsTer74 | frameshift_variant | 3/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.488del | p.Leu163ArgfsTer74 | frameshift_variant | 3/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.107del | p.Leu36ArgfsTer74 | frameshift_variant | 3/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.227del | p.Leu76ArgfsTer74 | frameshift_variant | 4/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-12797del | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460366Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726592
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2023 | Not observed in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 15466642, 15840476, 19716085, 19841300, 22677073, 31447099, 30122538, 33087929, 34319147) - |
Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 24, 2017 | The c.488del (p.Leu163Argfs*74) variant in the KCNE1 gene has been reported in a patient from a cohort of 388 patients referred for LQTS genetic testing with a family history of a first degree relative with a cardiac event during swimming [reported as V162fs in PMID 15840476, 15840476]. This variant has not been observed in the ExAC database but has been assessed in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/53050). This one bp deletion in exon 3 results in a frameshift and the creation of a premature stop codon, and is predicted to result in a loss of function of KCNQ1. This variant is thus classified as pathogenic - |
Jervell and Lange-Nielsen syndrome;C1141890:Congenital long QT syndrome;C5680250:Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2015 | The p.Leu163fs variant in KCNQ1 has been previously reported in at least 1 indiv idual with long QT syndrome and is absent from large population databases (Choi 2004, Tester 2005, Kapplinger 2009). This variant is predicted to cause a frames hift, which alters the protein's amino acid sequence beginning at codon 163 and leads to a premature stop codon 74 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function variants in KCNQ1 lead to Jervell and Lange-Nielsen syndrome (JLNS) in compound heterozy gous and homozygous individuals, while dominant-negative and loss-of-function va riants in KCNQ1 have been shown to cause dominantly inherited long QT syndrome 1 (also known as Romano-Ward syndrome)in heterozygous individuals. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant meets our criteria to be classified as likely pathogenic (http ://www.partners.org/personalizedmedicine/LMM) based upon its impact to the prote in. - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53050). This variant is also known as L163FS/X236. This premature translational stop signal has been observed in individuals with sudden unexplained death (PMID: 22677073). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu163Argfs*74) 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). - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2020 | The c.488delT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at position 488, causing a translational frameshift with a predicted alternate stop codon (p.L163Rfs*74). This mutation has been reported in patients referred for long QT syndrome clinical genetic testing; however, clinical details are limited (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at