NM_000218.3:c.1771C>A

Variant names:

• chr11-2778014-C-A
• NM_000218.3:c.1771C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000218.3(KCNQ1):​c.1771C>A​(p.Arg591Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.92

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.

• PM1: In a region_of_interest Interaction with AKAP9 (size 28) in uniprot entity KCNQ1_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2778014-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-2778014-C-A is Pathogenic according to our data. Variant chr11-2778014-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3235934.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1771C>A	p.Arg591Ser	missense_variant	Exon 15 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1771C>A	p.Arg591Ser	missense_variant	Exon 15 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Sep 15, 2022

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1771C>A variant in KCNQ1 has not previously been reported in the literature or public variant repositories (ClinVar and LOVD), and is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases.The c.1771C>A variant in KCNQ1 is located in exon 15 of this 16-exon gene, and is predicted to replace an evolutionarily conserved arginine amino acid with serine at position 591 in the coiled-coiled region of the encoded protein. In silico predictions are moderately in favor of damaging effect for the p.(Arg591Ser) variant [CADD v1.6 = 26, REVEL = 0.912]; however, there are no functional studies to support or refute these predictions. Variants affecting the same residue (p.(Arg591His), p.(Arg591Cys), p.(Arg591Leu)) and nearby residues (p.(Ala590Thr), p.(Gly589Asp), p.(Arg594Gln)) have been reported in the literature [PMID: 10024302, 17470695, 22949429, 23158531, 29622001, 31737537, 32383558, 34505893, 34860437] and ClinVar [ClinVar IDs: 3140, 53015, 53016, 53017, 53018, 200857] in individuals with long QT syndrome. Functional studies demonstrated reduced channel current activity for the p.Arg591His variant supporting the functional importance of the p.Arg591 residue [PMID: 16253915]. Based on available evidence this inherited heterozygous c.1771C>A p.(Arg591Ser) variant identified in KCNQ1 is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.63	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.5	D;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0020	D;.;D;.
Polyphen		0.99	D;.;D;.
Vest4		0.93
MutPred		0.89		Loss of MoRF binding (P = 0.0234);.;.;.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.94
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2799244;