rs397508104
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):βc.1893delβ(p.Arg632GlufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 1,574,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. G629G) has been classified as Likely benign.
Frequency
Consequence
NM_000218.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1893del | p.Arg632GlufsTer34 | frameshift_variant | 16/16 | ENST00000155840.12 | |
KCNQ1-AS1 | NR_130721.1 | n.778-7417del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1893del | p.Arg632GlufsTer34 | frameshift_variant | 16/16 | 1 | NM_000218.3 | P1 | |
KCNQ1-AS1 | ENST00000440887.2 | n.777-7417del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000703 AC: 10AN: 1422680Hom.: 0 Cov.: 31 AF XY: 0.00000994 AC XY: 7AN XY: 704064
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74448
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg632Glufs*34) 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. This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 16414944, 22739119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53026). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2023 | This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. - |
Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.1893del(p.Arg632GlufsTer34) in the KCNQ1 gene has been reported previously in a heterozygous state in individuals affected with Long QT syndrome. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (Egashira et al., 2012; Napolitano et al., 2005). This variant is reported with the allele frequency (0.004%) in the gnomAD Exomes. This variant causes a frameshift starting with codon Arginine 632, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 34 of the new reading frame. It is submitted to ClinVar as Pathogenic/ Likely pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2022 | Published functional studies using iPSCs and HEK293 cells suggest that that this variant has a dominant negative effect due to a trafficking deficiency (Egashira et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are replaced with 33 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #53026); This variant is associated with the following publications: (PMID: 19825999, 22739119, 16414944, 27026928, 27110425, 26669661, 30609406, 24657289, 27009425, 23444871, 29976690, 32231684, 34691145) - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 29, 2023 | This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at