rs794728549

Positions:

• chr11-2527923-T-A
• chr11-2527923-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.387-5T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.631

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-2527923-T-A is Pathogenic according to our data. Variant chr11-2527923-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2527923-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.387-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.387-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000218.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461534 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727088

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in skipping of exon 2 and introduces a premature termination codon (PMID: 19027783). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 200872). This variant has been observed in individuals with long QT syndrome (PMID: 28944242). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the KCNQ1 gene. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2022	Variant summary: KCNQ1 c.387-5T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 3' splice acceptor site. Two predict the variant weakens the canonical 3' splice acceptor site. Three predict the variant creates a new intronic 3' splice acceptor site at nucleotide c.387-5. At least one publication reports experimental evidence that this variant affects mRNA splicing with the majority of transcripts resulting in exon 2 skipping (example, Bhuiyan_2008). The variant was absent in 251336 control chromosomes. c.387-5T>A has been reported in the literature as a homozygous founder variant in at-least 5 consanguineous Saudi Arabian families with Long QT Syndrome and preserved normal hearing (example, Bhuiyan_2008, Bhuiyan_2009, Bdier_2017) and these studies continue to be cited by others in the field. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Bhuiyan_2008). The most pronounced variant effect results in non-functional mutant KCNQ1 + KCNE1 channels as determined by electrophysiological studies in a HEK-293 cell expression system. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, until families from additional ethnicities with this variant are identified, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 10, 2023	The c.387-5T>A variant of KCNQ1 has been reported in individuals with Long-QT syndrome (PMID: 28944242, PMID: 1918417). This variant is predicted to disrupt mRNA splicing (SpliceAI: 0.77). RNA studies have shown that this variant causes the skipping of exon 2 and introduces a premature termination codon, resulting in incomplete transcriptional aberration of the KCNQ1 gene (PMID: 19027783). This variant is not present in population databases (gnomAD no frequency). Based on this evidence, the c.387-5T>A variant of KCNQ1 is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	22
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.77		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: rs794728549; hg19: chr11-2549153;