rs199472676

Positions:

• chr11-2445315-C-A
• chr11-2445315-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000218.3(KCNQ1):​c.217C>A​(p.Pro73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,504,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2 O:1
• Conservation: PhyloP100: 1.34

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38735473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.217C>A	p.Pro73Thr	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.217C>A	p.Pro73Thr	missense_variant	1/15
KCNQ1	NM_001406838.1	c.217C>A	p.Pro73Thr	missense_variant	1/11
KCNQ1	NM_001406837.1	c.-146C>A		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.217C>A	p.Pro73Thr	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.217C>A	p.Pro73Thr	missense_variant	1/11
KCNQ1	ENST00000496887.7	c.24-68C>A		intron_variant		5
KCNQ1	ENST00000345015.4			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000859 AC: 13 AN: 151300 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000153 AC: 23 AN: 150334 Hom.: 0 AF XY: 0.000151 AC XY: 13 AN XY: 85862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000426

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: 0.000275

Gnomad OTH exome AF: 0.000813

GnomAD4 exome AF: 0.000215 AC: 291 AN: 1353216 Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 141 AN XY: 671114

Gnomad4 AFR exome AF: 0.0000349

Gnomad4 AMR exome AF: 0.0000573

Gnomad4 ASJ exome AF: 0.0000427

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000300

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000162

GnomAD4 genome AF: 0.0000859 AC: 13 AN: 151300 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73910

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000117 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2024	Reported in association with LQTS (PMID: 15840476, 20851114, 23098067, 24606995, 26743238); Also reported in individuals who harbor an additional pathogenic variant that could explain their phenotype (PMID: 24667783, 29598884, 28588847); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24606995, 23098067, 19716085, 25351510, 22949429, 19862833, 19841300, 26633542, 20851114, 26986070, 28595573, 28588847, 28988457, 29197658, 29598884, 33181513, 31737537, 24667783, 15840476, 26743238, 22581653, 32048431, RidaM2023[Preprint], 37937776, 37449562) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Long QT syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the KCNQ1 protein (p.Pro73Thr). This variant is present in population databases (rs199472676, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 15840476, 19716085, 22949429, 24606995, 24667783, 26743238, 28588847). ClinVar contains an entry for this variant (Variation ID: 53031). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Oct 23, 2015

- -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Short QT syndrome type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Oct 23, 2015

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 16, 2023

Variant summary: KCNQ1 c.217C>A (p.Pro73Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 150334 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Long QT Syndrome phenotype (8.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.217C>A has been reported in the literature in individuals affected with Long QT Syndrome (Example: Tester_2005, Kapa_2009, Kapplinger_2009, Marschall_2019, Millat_2011) etc . These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.87C>A, p.Phe29Leu; SCN5A c.1231G>A, p.Val411Met; KCNQ1 c.502G>A, P.Gly168Arg) (Mullertz_2018, Magnusson_2017, Riuro_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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;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	Benign	0.079
BayesDel_addAF	Benign	0.0080	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	7.3
DANN	Benign	0.81
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.57
Sift	Benign	0.037	D
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.75		Gain of phosphorylation at P73 (P = 0.0102);
MVP		0.80
MPC		1.3
ClinPred		0.036	T
GERP RS		-0.73
Varity_R		0.033
gMVP		0.22

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: rs199472676; hg19: chr11-2466545;