rs397508107

chr11-2445299-GGCCGCGCCC-Gchr11-2445299-GGCCGCGCCC-GGCCGCGCCCGCCGCGCCC

Variant summary

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

The NM_000218.3(KCNQ1):c.211_219del(p.Ala71_Pro73del) variant causes a 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 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 2.88

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 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	UniProt
KCNQ1	NM_000218.3	c.211_219del	p.Ala71_Pro73del	inframe_deletion	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.211_219del	p.Ala71_Pro73del	inframe_deletion	1/15
KCNQ1	NM_001406838.1	c.211_219del	p.Ala71_Pro73del	inframe_deletion	1/11
KCNQ1	NM_001406837.1	c.-152_-144del		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.211_219del	p.Ala71_Pro73del	inframe_deletion	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.211_219del	p.Ala71_Pro73del	inframe_deletion	1/11
KCNQ1	ENST00000496887.7	c.24-74_24-66del		intron_variant		5
KCNQ1	ENST00000345015.4			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150612 Hom.: 0 Cov.: 32

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: 13 AN: 1264666 Hom.: 0 AF XY: 0.00000804 AC XY: 5 AN XY: 621672

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: 1 AN: 150612 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73524

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:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 07, 2022	- -
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) -

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

Invitae

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508107; hg19: chr11-2466529;