rs120074188

chr11-2768902-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1573G>A(p.Ala525Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,744 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A525V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.45

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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 chr11-2768903-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67040.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-2768902-G-A is Pathogenic according to our data. Variant chr11-2768902-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2768902-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1573G>A	p.Ala525Thr	missense_variant	12/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1573G>A	p.Ala525Thr	missense_variant	12/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.1192G>A	p.Ala398Thr	missense_variant	12/16	1
KCNQ1	ENST00000496887.7	c.1216G>A	p.Ala406Thr	missense_variant	12/16	5
KCNQ1	ENST00000646564.2	c.1033G>A	p.Ala345Thr	missense_variant	7/11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251374 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2012

p.Ala525Thr (GCC>ACC): c.1573 G>A in exon 12 of the KCNQ1 gene (NM_000218.2). The Ala525Thr mutation in the KCNQ1 gene has been reported previously in association with LQTS (Larsen et al., 1999, Kapplinger et al., 2009). Larsen et al. reported Ala525Thr in one patient with neonatal onset LQTS who was compound heterozygous for a nonsense mutation in the KCNQ1 gene. Heterozygous carriers of the Ala525Thr mutation in this family were asymptomatic for clinical LQTS, suggesting an autosomal recessive form of LQTS. However, the proband's mother and sibling were heterozygous for this mutation and reportedly asymptomatic, but presented with a prolonged QTc intervals (Larsen et al., 1999). Kapplinger et al. also identified Ala525Thr in one Caucasian individual with LQTS and it was absent from 2,600 reference alleles. The NHLBI ESP Exome Variant Server reports Ala525Thr was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations (NHLBI ESP). Other mutations in this codon (Ala525Val) and in neighboring codons (Tyr522Ser, Val524Gly, Lys526Glu) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Therefore, Ala525Thr in the KCNQ1 gene is interpreted to be a disease-causing mutation. The variant is found in LQT panel(s). -

Long QT syndrome 1, recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 525 of the KCNQ1 protein (p.Ala525Thr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24912595). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 3132). This variant has been observed to be heterozygous in individual(s) with clinical features of long QT syndrome (PMID: 10482963, 22949429). However, in at least one family this variant was detected in unaffected relative(s). This variant has also been observed to be in combination with another KCNQ1 variant in individual(s) with isolated long QT syndrome, but without hearing loss typically associated with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 10482963). The clinical significance of this variant in autosomal recessive long QT syndrome is currently unknown. This variant is present in population databases (rs120074188, gnomAD 0.004%). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2016

The p.A525T variant (also known as c.1573G>A), located in coding exon 12 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1573. The alanine at codon 525 is replaced by threonine, an amino acid with similar properties. This alteration was first reported in two siblings who presented shortly after birth with bradycardia and prolonged QTc intervals and who both had a second nonsense alteration in trans in KCNQ1 (Larsen LA, Eur. J. Hum. Genet. 1999 Sep; 7(6):724-8). Further in vitro studies suggest the p.A525T alteration, when present in compound heterozygous state with a nonsense mutation, impacts protein processing and trafficking in the endoplasmic reticulum (ER); however, only mild impact was observed when this variant was present in heterozygous state (Harmer SC, Biochem. J. 2014 Aug; 462(1):133-42). In addition, this alteration was reported in studies of long QT syndrome clinical genetic testing; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Kapa S et al. Circulation. 2009 Nov 3;120(18):1752-60). This variant was previously reported in the SNPDatabase as rs120074188. Based on data from ExAC, the A allele has an overall frequency of approximately <0.01% (1/106061). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10482963;PMID:19716085;PMID:19841300). 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	0.93
CardioboostArm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.94		Gain of phosphorylation at A525 (P = 0.0485);.;.;
MVP		0.99
MPC		1.1
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.73
gMVP		0.97

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: rs120074188; hg19: chr11-2790132;