11-2583545-G-C

Position:

• chr11-2583545-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000218.3(KCNQ1):​c.1032G>C​(p.Ala344Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). 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 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.79

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2583545-G-C is Pathogenic according to our data. Variant chr11-2583545-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 52939.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2583545-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1032G>C	p.Ala344Ala	splice_region_variant, synonymous_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.1032G>C	p.Ala344Ala	splice_region_variant, synonymous_variant	7/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.651G>C	p.Ala217Ala	splice_region_variant, synonymous_variant	7/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.771G>C	p.Ala257Ala	splice_region_variant, synonymous_variant	8/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.588G>C	p.Ala196Ala	splice_region_variant, synonymous_variant	3/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2013

p.Ala344Ala (GCG>GCC): c.1032 G>C in exon 7 of the KCNQ1 gene (NM_000218.2). The c.1032 G>C mutation in the KCNQ1 gene has been reported to co-segregate with a LQTS phenotype in one family (Murray A et al., 1999). The c.1032 G>C mutation changes the last nucleotide in exon 7 of the KCNQ1 gene, which affects the donor splice site and results in exon skipping (Murray A et al., 1999). Furthermore, a different nucleotide change at the same codon (c.1032 G>A, Ala344Ala) also has been reported to affect the donor splice site, and it has been reported in association with LQTS (Murray A et al., 1999). The c.1032 G>C mutation 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.In summary, c.1032 G>C in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		Position offset: 15
DS_DL_spliceai		0.55		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800171; hg19: chr11-2604775;