rs878854350

Positions:

• chr11-2776984-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000155840.12(KCNQ1):​c.1686-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000274 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNQ1 ENST00000155840.12 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.41

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.2, offset of 47, new splice context is: actgttcatctccgtctcAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2776984-A-G is Pathogenic according to our data. Variant chr11-2776984-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1686-2A>G		splice_acceptor_variant		ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1686-2A>G		splice_acceptor_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.1305-2A>G		splice_acceptor_variant		1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.1329-2A>G		splice_acceptor_variant		5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.1146-2A>G		splice_acceptor_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2011	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the compound heterozygous state with another KCNQ1 variant in an individual with long QT syndrome (Vyas et al., 2016a; Vyas et al., 2016b); This variant is associated with the following publications: (PMID: 34319147, 27485560, 27041150) -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 09, 2017	- -

Long QT syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2024	Variant summary: KCNQ1 c.1686-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251050 control chromosomes (gnomAD). c.1686-2A>G has been reported in the literature in individuals affected with Autosomal Recessive RomanoWard Syndrome or Long QT Syndrome (Vyas_2016, Choi_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27041150, 34319147). ClinVar contains an entry for this variant (Variation ID: 207973). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 17, 2021	This sequence change affects an acceptor splice site in intron 13 of the KCNQ1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in KCNQ1 are known to be pathogenic (PMID: 19862833). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported in the literature in a individual affected with a recessive form of long QT syndrome (PMID: 27041150). ClinVar contains an entry for this variant (Variation ID: 207973). This variant is not present in population databases (ExAC no frequency). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2020

The c.1686-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 14 in the KCNQ1 gene. This variant was reported in an individual with Romano-Ward syndrome, who was a compound heterozygote with an additional KCNQ1 alteration (p.R533W, c.1597C>T); the proband's father had a QTc of 415ms and was reported to be heterozygous for the c.1686-2A>G variant (Vyas B et al. Am. J. Med. Genet. A, 2016 Jun;170:1510-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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 likely pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854350; hg19: chr11-2798214;