rs794728559
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5
The NM_000218.3(KCNQ1):c.1029_1031dup(p.Ala344_Gly344insAla) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ1
NM_000218.3 inframe_insertion
NM_000218.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.38
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000218.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000218.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 11-2583540-C-CCAG is Pathogenic according to our data. Variant chr11-2583540-C-CCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200885.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1029_1031dup | p.Ala344_Gly344insAla | inframe_insertion | 7/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1029_1031dup | p.Ala344_Gly344insAla | inframe_insertion | 7/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.648_650dup | p.Ala217_Gly217insAla | inframe_insertion | 7/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.768_770dup | p.Ala257_Thr257insAla | inframe_insertion | 8/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.585_587dup | p.Ala196_Thr196insAla | inframe_insertion | 3/11 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2014 | This variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The c.1029_1031dupAGC variant results in insertion of nucleotides AGC, which maintains the reading frame and results in duplication of the Alanine at position 344. While the c.1029_1031dupAGC variant is not predicted by in silico algorithms to affect splicing, two other variants at this residue (A344E and A344V) have been reported in association with LQTS. Alanine 344 is located in the S6 transmembrane domain of the KCNQ1 protein, which hosts many other arrhythmia-associated missense variants. This substitution occurs at a position that is conserved across species. The KCNQ1 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other in frame duplications in the KCNQ1 gene have been reported in association with LQTS. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 200885). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1029_1031dup, results in the insertion of 1 amino acid(s) of the KCNQ1 protein (p.Ala344dup), but otherwise preserves the integrity of the reading frame. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at