NM_000218.3:c.381C>A

Variant names:

• chr11-2445479-C-A
• rs199472682
• NM_000218.3:c.381C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000218.3(KCNQ1):​c.381C>A​(p.Phe127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.220

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 21) in uniprot entity KCNQ1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.381C>A	p.Phe127Leu	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.381C>A	p.Phe127Leu	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406837.1	c.19C>A	p.Arg7Ser	missense_variant	Exon 1 of 17		NP_001393766.1
KCNQ1	NM_001406838.1	c.381C>A	p.Phe127Leu	missense_variant	Exon 1 of 11		NP_001393767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.381C>A	p.Phe127Leu	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000345015.4	n.158C>A		non_coding_transcript_exon_variant	Exon 1 of 3	1
KCNQ1	ENST00000496887.7	c.120C>A	p.Phe40Leu	missense_variant	Exon 2 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.381C>A	p.Phe127Leu	missense_variant	Exon 1 of 11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442646 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717798

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.88	.;D;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Pathogenic	0.65
Sift	Benign	0.70	T;T;.
Sift4G	Benign	0.47	T;T;.
Polyphen		0.13	.;B;.
Vest4		0.90
MutPred		0.78		.;Loss of catalytic residue at C122 (P = 0.1895);.;
MVP		0.92
MPC		1.8
ClinPred		0.98	D
GERP RS		-1.2
Varity_R		0.81
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199472682; hg19: chr11-2466709;