chr11-2661960-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PP3_ModeratePP5_Very_Strong
The NM_000218.3(KCNQ1):c.1394-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000356 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
KCNQ1
NM_000218.3 splice_acceptor
NM_000218.3 splice_acceptor
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 5.59
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]
KCNQ1OT1 (HGNC:6295): (KCNQ1 opposite strand/antisense transcript 1) Human chromosomal region 11p15.5 contains two clusters of epigenetically-regulated genes that are expressed from only one chromosome in a parent-of-origin manner. Each cluster, or imprinted domain, is regulated by a functionally independent imprinting control region (ICR). The human CDKN1C/KCNQ1OT1 domain is regulated by an ICR located in an intron of KCNQ1, and contains at least eight genes that are expressed exclusively or preferentially from the maternally-inherited allele. The DNA of the ICR is specifically methylated on the maternally-inherited chromosome, and unmethylated on the paternally-inherited chromosome. The ICR contains the promoter of the KCNQ1OT1 gene that is exclusively expressed from the paternal allele. The KCNQ1OT1 transcript is the antisense to the KCNQ1 gene and is a unspliced long non-coding RNA. It interacts with chromatin and regulates transcription of multiple target genes through epigenetic modifications. The transcript is abnormally expressed from both chromosomes in most patients with Beckwith-Wiedemann syndrome, and the transcript also plays an important role in colorectal carcinogenesis. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.3, offset of 4, new splice context is: cacactttctcctcattaAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-2661960-G-T is Pathogenic according to our data. Variant chr11-2661960-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 200847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2661960-G-T is described in Lovd as [Pathogenic]. Variant chr11-2661960-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1394-1G>T | splice_acceptor_variant | ENST00000155840.12 | |||
KCNQ1OT1 | NR_002728.3 | n.38039C>A | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1394-1G>T | splice_acceptor_variant | 1 | NM_000218.3 | P1 | |||
KCNQ1OT1 | ENST00000710656.1 | n.376-20845C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251392Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461854Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 727222
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: 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 | GeneDx | Jul 24, 2023 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual diagnosed with severe LQTS who also harbored a frameshift variant in the KCNH2 gene (Chung et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 19862833, 9323054, 23631430, 26318259, 34135346, 34319147, 17905336, 33087929) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 31, 2013 | 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 IVS10-1G>T (c.1394-1G>T) Based on the data reviewed below, we consider it likely disease-causing. This variant has been seen in at least one published case in the literature. We have also found it segregating with LQTS in one family at our center. Chung et al. 2007 identified this splice variant in addition to a frameshift insertion in KCNH2 in a patient with “severe LQTS”. In terms of clinical details, this patient was Caucasian, had a personal history of syncope and a family history of SCD in a first degree relative, and had a QTc of 520 ms. Her diagnosis was described as “LQT1/LQT2”). It was absent from 50 control individuals in this study. This variant is very likely to disrupt normal splicing, as it changes the last base of intron 10 from a G to a T thus destroying the canonical G nucleotide of the splice acceptor site. There are several splice, nonsense and frameshift variants that have been associated with LQTS in the literature, including nearby splicing variants also in the c-terminus (922-1G>C; 1251+2T>C; 1514+1G>A). In total, this variant has not been seen in approximately 6,650 publicly available population and laboratory controls (including ~6,500 individuals of African American and European ancestry from NHLBI ESP dataset; 100 Caucasian individuals from GeneDx; and 50 individuals from Chung et al. 2007). There is a variant involving this same splice acceptor site seen in 6 individuals in ESP, however it is at the -8 position (thus unlikely to have the same effect as changing the canonical splice acceptor site). This variant has also not been observed in the 1000Genomes dataset or dbSNP as of October 31, 2013. This variant is currently present in HGMD and LOVD as a disease-causing mutation on the basis of the Chung et al. 2007 variant. - |
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2017 | Variant summary: The KCNQ1 c.1394-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was found in the control population dataset of ExAC in 1/121208 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). This variant was reported in multiple patients with LQTS in the literature (Chung_2007, Lieve_2013, Ruwald_2016) and was stated as segregating with LQTS in a family (Stanford Center for Inherited Cardiovascular Disease). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2023 | This sequence change affects an acceptor splice site in intron 10 of the KCNQ1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is present in population databases (rs775537394, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with long QT syndrome (PMID: 17905336, 23631430, 26318259; Invitae). This variant is also known as IVS10-1G>T. ClinVar contains an entry for this variant (Variation ID: 200847). 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. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2021 | The c.1394-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 11 of the KCNQ1 gene. This alteration (also referred to as IVS10-1G>T) has been detected in a subject with long QT syndrome (LQTS) who also carried a second frameshift alteration in KCNH2 (Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14). This alteration was also reported in additional LQTS cohorts; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Ruwald MH et al. Heart Rhythm. 2016 Jan;13(1):122-31). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 30, 2023 | This variant causes a G to T nucleotide substitution at the -1 position of intron 10 (also known as IVS10-1G>T) of the KCNQ1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been observed in multiple individuals affected with or suspected of having long QT syndrome (PMID: 17905336, 23631430, 26318259, ClinVar SCV000280145.1, communication with external laboratories: SCV000752693.7, SCV000234493.16, SCV000738035.4). It has been reported that this variant segregates with disease in at least one of the families (communication with an external laboratory ClinVar SCV000234493.16). This variant has also been reported in a healthy individual aged 70 years or older without a history of coronary heart disease (PMID: 34135346). This variant has been identified in 1/251392 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
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at