rs1554919471

Positions:

• chr11-2768860-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000218.3(KCNQ1):​c.1534delG​(p.Ala512fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.44

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2768860-CG-C is Pathogenic according to our data. Variant chr11-2768860-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 430941.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2768860-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1534delG	p.Ala512fs	frameshift_variant	12/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1534delG	p.Ala512fs	frameshift_variant	12/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1153delG	p.Ala385fs	frameshift_variant	12/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1177delG	p.Ala393fs	frameshift_variant	12/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.994delG	p.Ala332fs	frameshift_variant	7/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biotechnology Research Center, Pasteur Institute of Iran

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According to the ACMG standards and guidelines these findings are evidence of pathogenicity. 1: The mutation in the family was a LOF in the KCNQ1 gene where LOF is a known mechanism of JLNS (PVS1). 2: The mutation has never been reported in ExAC or 1000G (PM2) 3: this KCNQ1 gene mutation results in the truncated protein (PM4) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554919471; hg19: chr11-2790090;