chr11-2588717-AG-A

Position:

• chr11-2588717-AG-A

Variant summary

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

The NM_000218.3(KCNQ1):​c.1257del​(p.Lys422SerfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K419K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.36

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: 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 11-2588717-AG-A is Pathogenic according to our data. Variant chr11-2588717-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 526930.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1257del	p.Lys422SerfsTer10	frameshift_variant	10/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1257del	p.Lys422SerfsTer10	frameshift_variant	10/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.876del	p.Lys295SerfsTer10	frameshift_variant	10/16	1
KCNQ1	ENST00000496887.7	c.900del	p.Lys303SerfsTer10	frameshift_variant	10/16	5
KCNQ1	ENST00000646564.2	c.717del	p.Lys242SerfsTer10	frameshift_variant	5/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Feb 02, 2018

Variant KCNQ1, Exon 10, p.Lys422Serfs*10 (c.1257delG) NM_000218. SCICD classification Likely pathogenic We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: type of variation in this gene well demonstrated to cause disease, sufficiently rare, same protein change observed in cases. Gene-level evidence Strong evidence associated KCNQ1 with long QT, including other frameshift and loss of function variants. Predicted effect KCNQ1 has 16 exons. Given this frameshift falls in the middle of the gene it likely leads to nonsense mediated decay. Case data summary Per the lab report, none reported with this specific DNA change. However, "A different variant (c.1265delA) giving rise to the same protein effect observed here (p.Lys422Serfs*10) hasreported in individuals affected with long QT syndrome (PMID: 19716085, 19841300, 23098067,, 22456477)" Population Data Absent in gnomAD, however same protein change due to a neighboring nucleotide change (c.1265delA) is present in three gnomAD populations with highest MAF 0.006582% in Africans. cardioclassifier.org suggests a cut off of MAF 0.0008% for LQTS. Note the variant is only identified once in each of these populations so the error bars on the estimate of the MAF are large. Please see below for details. Population data: The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 30x whereas in exomes it is 76x. However, c.1265delA is listed in gnomAD, MAF 0.006582% in Africans, 0.0008994% in Europeans (non-Finnish), 0.003262% in South Asians). Cardioclassifier.org suggests a cut off of MAF 0.0008% for LQTS. Note the variant is only identified once in each of these populations so the error bars on the estimate of the MAF are large. https://varsome.com/variant/hg19/chr11-2609949-A- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). A different variant (c.1265delA) giving rise to the same protein effect observed here (p.Lys422Serfs*10) has been reported in individuals affected with long QT syndrome (PMID: 19716085, 19841300, 23098067, 14998624, 22456477), indicating that this residue may be critical for protein function. This variant has not been reported in the literature in individuals with KCNQ1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys422Serfs*10) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. -

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: rs1554895166; hg19: chr11-2609947;