rs794728559

Positions:

• chr11-2583540-C-CCAG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000218.3(KCNQ1):​c.1029_1031dupAGC​(p.Ala344dup) variant causes a disruptive inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A344A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 disruptive_inframe_insertion, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.38

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 19) in uniprot entity KCNQ1_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-2583540-C-CCAG is Pathogenic according to our data. Variant chr11-2583540-C-CCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200885.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1029_1031dupAGC	p.Ala344dup	disruptive_inframe_insertion, splice_region_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1029_1031dupAGC	p.Ala344dup	disruptive_inframe_insertion, splice_region_variant	7/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.648_650dupAGC	p.Ala217dup	disruptive_inframe_insertion, splice_region_variant	7/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.768_770dupAGC	p.Ala257dup	disruptive_inframe_insertion, splice_region_variant	8/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.585_587dupAGC	p.Ala196dup	disruptive_inframe_insertion, splice_region_variant	3/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2014

This variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The c.1029_1031dupAGC variant results in insertion of nucleotides AGC, which maintains the reading frame and results in duplication of the Alanine at position 344. While the c.1029_1031dupAGC variant is not predicted by in silico algorithms to affect splicing, two other variants at this residue (A344E and A344V) have been reported in association with LQTS. Alanine 344 is located in the S6 transmembrane domain of the KCNQ1 protein, which hosts many other arrhythmia-associated missense variants. This substitution occurs at a position that is conserved across species. The KCNQ1 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other in frame duplications in the KCNQ1 gene have been reported in association with LQTS. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 200885). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1029_1031dup, results in the insertion of 1 amino acid(s) of the KCNQ1 protein (p.Ala344dup), but otherwise preserves the integrity of the reading frame. -

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: rs794728559; hg19: chr11-2604770;