rs794728557

Positions:

• chr11-2572981-GGGGTGGTAAGTC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000155840.12(KCNQ1):​c.919_921+9del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G306G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 ENST00000155840.12 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts 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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06893156 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2572981-GGGGTGGTAAGTC-G is Pathogenic according to our data. Variant chr11-2572981-GGGGTGGTAAGTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572981-GGGGTGGTAAGTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.919_921+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.919_921+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.538_540+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.658_660+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-10451_478-10440del		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460654 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726516

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2016	The c.919_921+9del12 variant in the KCNQ1 gene has not been reported to our knowledge. The c.919_921+9del12 variant results in a 12-bp deletion of the exonic GTG nucleotides and intronic gtaagtcgg nucleotides spanning an exon-intron boundary. This variant is expected to destroy the splice donor site of intron 6. The c.919_921+9del12 variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While the c.919_921+9del12 variant has not been published, it is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728557; hg19: chr11-2594211;