11-2583434-G-C

Variant names:

• chr11-2583434-G-C
• rs387906290
• NM_000218.3:c.922-1G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000218.3(KCNQ1):​c.922-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.36

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05465288 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of 7, new splice context is: cctctccctgcacgtcacAGtca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2583434-G-C is Pathogenic according to our data. Variant chr11-2583434-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3134.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2583434-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.922-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.922-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 15	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.541-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 15	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.661-1G>C		splice_acceptor_variant, intron_variant	Intron 7 of 15	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-1G>C		splice_acceptor_variant, intron_variant	Intron 2 of 10			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Sep 07, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Long QT syndrome Pathogenic:1

Jul 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disruption of this splice site has been observed in individuals with long QT syndrome (PMID: 10477533; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the KCNQ1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. ClinVar contains an entry for this variant (Variation ID: 3134). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exons 7 and 8 (also referred to as exons 6 and 7), but is expected to preserve the integrity of the reading-frame (PMID: 10477533). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Pathogenic	0.89
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.83	D
GERP RS		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 8
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906290; hg19: chr11-2604664;