11-2445299-GGCCGCGCCC-G

Position:

chr11-2445299-GGCCGCGCCC-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_000218.3(KCNQ1):c.211_219delGCCGCGCCC(p.Ala71_Pro73del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000989 in 1,415,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 2.88

Variant links:

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]

KCNQ1 links:

KCNQ1 (HGNC:):

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000218.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.211_219delGCCGCGCCC	p.Ala71_Pro73del	conservative_inframe_deletion	1/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 linkuse as main transcript	c.211_219delGCCGCGCCC	p.Ala71_Pro73del	conservative_inframe_deletion	1/15		NP_001393765.1
KCNQ1	NM_001406838.1 linkuse as main transcript	c.211_219delGCCGCGCCC	p.Ala71_Pro73del	conservative_inframe_deletion	1/11		NP_001393767.1
KCNQ1	NM_001406837.1 linkuse as main transcript	c.-152_-144delGCCGCGCCC		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.211_219delGCCGCGCCC	p.Ala71_Pro73del	conservative_inframe_deletion	1/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.211_219delGCCGCGCCC	p.Ala71_Pro73del	conservative_inframe_deletion	1/11			ENSP00000495806.2	A0A2R8YEQ9
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.24-74_24-66delGCCGCGCCC		intron_variant		5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000345015.4 linkuse as main transcript	n.-22_-14delGCCGCGCCC		upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000485

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1264666

Hom.:

AF XY:

0.00000804

AC XY:

AN XY:

621672

show subpopulations

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:

0.0000165

Gnomad4 FIN exome

AF:

0.0000339

Gnomad4 NFE exome

AF:

0.00000980

Gnomad4 OTH exome

AF:

0.0000194

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150612

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73524

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000485

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2022	Has been described in a 19 year-old female who died after a near-drowning incident (Ackerman et al., 1999). Although this variant was also identified in the proband's sister, mother, and maternal grandfather, who all had prolonged or borderline QTcs, the proband and her sister were subsequently found to harbor the p.(V524G) likely pathogenic variant in the KCNQ1 gene that likely contributed to the phenotype (Choi et al., 2004).; Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12877697, 15466642, 10511610, 29582136) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 07, 2022	- -

Long QT syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 07, 1999

- -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This variant, c.211_219del, results in the deletion of 3 amino acid(s) of the KCNQ1 protein (p.Ala71_Pro73del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with long QT syndrome (PMID: 10511610). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3130). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2018

The c.211_219delGCCGCGCCC variant (also known as p.A71_P73del) is located in coding exon 1 of the KCNQ1 gene. This variant results from an in-frame deletion of 9 nucleotides at positions 211 to 219. This results in the deletion of 3 amino acids between codons 71 and 73. This variant has been described in an individual from Mayo Clinic genetic testing cohorts who suffered a swimming-related sudden cardiac death with documented prolonged QTc measurements and electrolyte imbalances following the event, and who also had an additional KCNQ1 missense variant by some reports (Ackerman MJ et al. N. Engl. J. Med., 1999 Oct;341:1121-5; Nemec J et al. Pacing Clin Electrophysiol, 2003 Aug;26:1660-7; Choi G et al. Circulation, 2004 Oct;110:2119-24; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17). The in-frame deletion was also detected in the individual's mother with prolonged QTc, but without characteristic T-wave findings, and in her sister with a borderline prolonged QTc; however, no information regarding testing for an additional KCNQ1 variant was provided (Ackerman MJ et al. N. Engl. J. Med., 1999 Oct;341:1121-5). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over