chr11-2585300-T-A

Position:

• chr11-2585300-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1121T>A​(p.Leu374His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,374 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • 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:6 O:1
• Conservation: PhyloP100: 7.48

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 16 ACMG points.

• PM1: In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 25 pathogenic changes around while only 1 benign (96%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-2585300-T-A is Pathogenic according to our data. Variant chr11-2585300-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2585300-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1121T>A	p.Leu374His	missense_variant	8/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1121T>A	p.Leu374His	missense_variant	8/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.740T>A	p.Leu247His	missense_variant	8/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.771+1755T>A		intron_variant		5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.588+1755T>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251078 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461374 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 22, 2024	PP1_strong, PP3, PS3_mod, PS4_strong -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 20, 2016	p.Leu374His (L374H; c.1121T>A) in exon 8 of the KCNQ1 gene (NM_000218.2) We care for another LQTS family in which it segregates extensively with disease. Based on the information reviewed below, we classify it as Likely Disease Causing, concluding that there is sufficient evidence for its pathogenicity to warrant using it for diagnosis and for predictive genetic testing in at-risk family members. This variant has previously been reported in two unrelated individuals tested for LQTS (Tester et al. 2005; Kapplinger et al. 2009), with no published segregation data. However, we have seen it segregate in 6 affected members of a family with LQTS, across 5 meioses, which would happen by chance in only 3% (1/32) of cases. (Additionally, it was absent from two family members who showed no LQTS phenotype.) Per personal communication, there are also 11 cases at genetic testing labs. In the literature: Kapplinger et al. (2009) identified the Leu374His variant in one individual undergoing clinical genetic testing for LQTS. This individual was among the first 2500 people referred for clinical long QT genetic testing at Familion laboratory. Of note, there is no phenotypic data available for this cohort. The low variant yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen along with another variant (9% of the cohort had multiple variants), complicate analysis. Tester et al. (2005) identified it in a patient referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS testing. Leu374His results in a non-conservative amino acid substitution of a non-polar Leucine with a positively charged Histidine at a residue that is conserved across species. Variation at nearby residues +/- 10 has been associated with LQTS, which may support the functional importance of this region of the protein: Asn365His, Arg366Gln, Arg366Pro, Arg366Trp, Gln367His, Ala371Thr, Ala372Asp, Ser373Pro, Trp379Arg, Trp379Gly, Trp379Ser, Arg380Gly, Arg380Ser, (HGMD professional version as of January 17, 2014). According to the Invitae report, Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant may cause disease. However, when Kapa et al. (2009) compared 388 "clinically definite" LQTS probands to ~1300 healthy controls, they found that while controls do have variants in all regions of the protein, LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). p.Leu374His is in the cytoplasmic domain of the protein, in which missense variants are 22x more frequent in LQTS cases than in controls (Kapa et al. 2009). In total the variant has not been seen in >60,000 published controls and individuals from publicly available population datasets. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 4/20/2016. Variation at this codon has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Lati -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro functional studies suggest this variant may damage channel function; however, additional studies are needed to validate the effect of this variant (PMID: 31899541); 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: 19716085, 22581653, 30669290, 28569743, 30937429, 26659599, 15840476, 38255832, 31899541) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 374 of the KCNQ1 protein (p.Leu374His). This variant is present in population databases (rs199472767, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 31899541; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52961). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 31899541). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2023

The p.L374H pathogenic mutation (also known as c.1121T>A), located in coding exon 8 of the KCNQ1 gene, results from a T to A substitution at nucleotide position 1121. The leucine at codon 374 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in more than ten individuals with prolonged QT intervals and other phenotypes consistent with long QT syndrome and has been shown to segregate with disease in one family (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Hammami Bomholtz S et al. Pacing Clin Electrophysiol, 2020 02;43:210-216; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). Functional studies suggest that this alteration altered ion channel function (Hammami Bomholtz S et al. Pacing Clin Electrophysiol, 2020 02;43:210-216). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 02, 2023

This missense variant replaces leucine with histidine at codon 374 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a. 349-391) in the C-terminal cytoplasmic domain. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes retention of the channels in the endoplasmic reticulum and complete loss of potassium current (PMID: 31899541). This variant has been reported in over ten unrelated individuals affected with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 15840476, 19716085, 31899541, ClinVar SCV000737968.4, SCV000073978.8, SCV000280141.2, SCV000234478.14). It has also been shown that this variant segregates with long QT syndrome in six individuals from a family (PMID: 31899541). This variant has been identified in 1/251078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as 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:15840476;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	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.84		Gain of disorder (P = 0.0256);.;
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.98

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: rs199472767; hg19: chr11-2606530;