rs120074187

chr11-2572963-G-Achr11-2572963-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

The NM_000218.3(KCNQ1):c.898G>A(p.Ala300Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,624 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A300E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:11 O:1
• Conservation: PhyloP100: 9.29

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 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572964-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 11-2572963-G-A is Pathogenic according to our data. Variant chr11-2572963-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3128.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Uncertain_significance=8, Likely_pathogenic=2}. Variant chr11-2572963-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.898G>A	p.Ala300Thr	missense_variant	6/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.898G>A	p.Ala300Thr	missense_variant	6/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.517G>A	p.Ala173Thr	missense_variant	6/16	1
KCNQ1	ENST00000496887.7	c.637G>A	p.Ala213Thr	missense_variant	7/16	5
KCNQ1	ENST00000646564.2	c.478-10472G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000480 AC: 12 AN: 249914 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461390 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727012

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 08, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 11, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Bioinformatics dept., Datar Cancer Genetics Limited, India	Jun 01, 2017	- -

not provided Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	Identified in patients with LQTS referred for genetic testing at GeneDx and in published literuture (Burgos et al., 2016; Scwartz et al., 2021); at least one patient harbored additional cardiogenetic variants; Identified in the homozygous state in a 9-year-old boy with LQTS but no history of hearing loss; both consanguineous parents of the proband were heterozyous for A300T and did not have features of LQTS (Priori et al., 1998); Published functional studies demonstrated that the A300T variant reduces the Iks current, but does not show a dominant-negative effect (Priori et al., 1998; Bianchi et al., 2000). Furthermore, Bianchi et al (2000) reported that the presence of a heterozygous A300T variant is associated with a mild cellular phenotype and mild clinical presentation; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17999538, 19841300, 23591039, 19862833, 9927399, 14678125, 22949429, 12205113, 11530094, 27041150, 29021305, 29033053, 29197658, 30571187, 9641694, 33693037, 34505893, 11087258, 27251404, 28600177) -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:9641694;PMID:14678125;PMID:19841300;PMID:9927399;PMID:17999538). -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Long QT syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces alanine with threonine at codon 300 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes a reduced cell current, a hyperpolarizing shift in activation, and a faster activation rate of the channel (PMID: 9641694, 11087258, 30571187, 33693037). This variant has been reported in an individual affected with sudden unexplained death (PMID: 28600177), in at least three unrelated individuals affected with long QT syndrome including one homozygous boy with normal hearing whose parents were consanguineous, both heterozygous for A300T and with normal QT interval and no symptoms, and one individual with severe phenotype who also carried another de novo pathogenic variant in the KCNQ1 gene (PMID: 9641694, 27251404, 32268277, 32893267), and in five asymptomatic family members (PMID: 9641694, 27251404, 28600177). This variant has also been reported in another two unrelated healthy individuals (PMID: 19841300, 22949429). This variant has been identified in 12/249914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 300 of the KCNQ1 protein (p.Ala300Thr). This variant is present in population databases (rs120074187, gnomAD 0.03%). This missense change has been observed in individuals with autosomal dominant long QT syndrome and/or autosomal recessive long QT syndrome or unexpected sudden death without hearing loss typically associated with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 9641694, 27251404, 28600177, 34505893; Invitae). ClinVar contains an entry for this variant (Variation ID: 3128). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9641694, 11087258, 30571187, 33693037). This variant disrupts the p.Ala300 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 30, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 18, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ala300Thr Ala300Thr was previously reported in a 9-year-old boy with LQTS who was homozygous for the variant but did not exhibit the hearing loss typical of recessive Jervell and Lange-Nielsen syndrome (Priori et al. 1998). The boy’s parents were consanguineous, and they each carried a single copy of Ala300Thr but did not show features of LQTS. (Note: It is also present in PhenCode, which points to an entry in the Long QT Syndrome Database from a group in Denmark.) This is a non-conservative amino acid change, resulting in the replacement of an alanine (nonpolar) with a threonine (polar). Alanine at this location is highly conserved across mammalian species (conserved in 7 of 8 mammalian species). The adjacent residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.000. Functional studies by Bianchi et al. (2000) reportedly demonstrate that Ala300Thr reduces the potassium current of the channel but does not show a dominant negative effect. Priori et al. (1998) report that functional evaluation of mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate consistent with a mild mutation likely to require homozygosity to manifest the phenotype. Variants in nearby residues (Ala302Glu, Ala302Thr, Ala302Val, Leu303Pro) have been reported in association with LQTS, supporting the functional importance of this region of the protein. In total the variant has been seen in at least 1/7700 individuals from published controls and publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4000 Caucasian and ~2000 African American individuals (as of November 13, 2013). There is also no variation at this codon listed in 1000 genomes. This variant has been reported in dbSNP. The variant was also identified in 1 published control individual (of Asian descent) out of ~1700 tested: 0/100 tested by Priori et al., 1/1300 tested by Kapa et al. -

Atrial fibrillation, familial, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 11, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jervell and Lange-Nielsen syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 11, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2021

The p.A300T variant (also known as c.898G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 898. The alanine at codon 300 is replaced by threonine, an amino acid with similar properties, and is located in the pore region. This variant has been reported in homozygous individuals with clinical diagnoses of long QT syndrome (LQTS) in the presence of normal hearing, thus atypical of autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). In these families, this variant has been detected in unaffected heterozygous relatives, suggesting an autosomal recessive cardiovascular phenotype or co-segregation with incomplete penetrance (Priori SG et al. Circulation, 1998 Jun;97:2420-5; Riuró H et al. Eur J Hum Genet. 2015 Jan;23:79-85). In another study, this variant was observed to occur in conjunction with a different de novo alteration in KCNQ1 and an alteration in SCN5A in an individual described as having severe LQTS phenotype (Burgos M et al. Mol Diagn Ther. 2016;20:353-62). This variant was also detected in the compound heterozygous state with a second KCNQ1 variant in a sudden death case where heterozygous relatives with p.A300T only were unaffected (Antúnez-Argüelles E et al. Gene. 2017 Sep;627:40-48). In functional in vitro analyses, this variant resulted in decreased channel currents, but did not result in dominant negative effects, consistent with an autosomal recessive inheritance pattern (Priori SG et al 1998; Bianchi L et al. Am J Physiol Heart Circ Physiol. 2000;279:H3003-11; González-Garrido A et al. Front Cardiovasc Med. 2021 Feb;8:625449). 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 available evidence, this variant may have clinical impact when present in the homozygous or compound heterozygous state; however, autosomal recessive inheritance of KCNQ1-related LQTS without hearing loss is not well-established, and the clinical impact of this variant in the heterozygous state remains unclear. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 16, 2022

This missense variant replaces alanine with threonine at codon 300 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes a reduced cell current, a hyperpolarizing shift in activation, and a faster activation rate of the channel (PMID: 9641694, 11087258, 30571187, 33693037). This variant has been reported in individuals affected with sudden unexplained death (PMID: 28600177), Jervell and Lange-Nielsen syndrome (PMID: 34165182), or long QT syndrome (PMID: 9641694, 27251404, 32268277, 32893267). One of these individuals also carried another de novo pathogenic variant in the KCNQ1 gene (PMID: 27251404). This variant has also been observed in asymptomatic family members (PMID: 9641694, 27251404, 28600177) and healthy individuals (PMID: 19841300, 22949429). This variant has been identified in 12/249914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MVP		0.98
MPC		1.1
ClinPred		0.78	D
GERP RS		3.9
Varity_R		0.93
gMVP		0.95

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: rs120074187; hg19: chr11-2594193;