rs199472701

Variant names:

• chr11-2570745-T-G
• rs199472701
• NM_000218.3:c.595T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000218.3(KCNQ1):​c.595T>G​(p.Ser199Ala) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.57

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 11-2570745-T-G is Pathogenic according to our data. Variant chr11-2570745-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 67090.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2570745-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.595T>G	p.Ser199Ala	missense_variant	Exon 3 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.595T>G	p.Ser199Ala	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.214T>G	p.Ser72Ala	missense_variant	Exon 3 of 16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.334T>G	p.Ser112Ala	missense_variant	Exon 4 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-12690T>G		intron_variant	Intron 2 of 10			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Jun 08, 2022

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595T>G p.(Ser199Ala) missense variant identified in exon 3 (of 16) of KCNQ1 has been previously reported in an individual with long QT syndrome[PMID:19716085], and it has also been deposited in ClinVar without pathogenicity classification [Variation ID: 67090]. The variant is absent from population databases (gnomADv2, gnomADv3, TOPMed Freeze 8) suggesting it is not a common benign variant in populations represented in those databases. The variant affects an evolutionarily conserved residue and in silico predictions are in favor of deleterious effect of the c.595T>G p.(Ser199Ala) variant on the encoded protein (REVEL score= 0.799); however, there are no functional studies to support or refute these predictions. Based on the available evidence, the c.595T>G p.(Ser199Ala)missense variant identified in the KCNQ1 gene is reported as a Variant of Uncertain Significance. -

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	Benign	0.23
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.68	.;N;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.10	T;D;D
Polyphen		0.20	.;B;.
Vest4		0.80, 0.79
MutPred		0.91		.;Loss of MoRF binding (P = 0.0996);.;
MVP		0.97
MPC		0.80
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.80
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs199472701; hg19: chr11-2591975;