11-2583471-C-T

Position:

• chr11-2583471-C-T

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.958C>T​(p.Pro320Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,570 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. P320A) has been classified as 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 U:1 O:1
• Conservation: PhyloP100: 7.42

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 intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNQ1_HUMAN there are 54 pathogenic changes around while only 0 benign (100%) 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 chr11-2583471-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-2583471-C-T is Pathogenic according to our data. Variant chr11-2583471-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583471-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.958C>T	p.Pro320Ser	missense_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.958C>T	p.Pro320Ser	missense_variant	7/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.577C>T	p.Pro193Ser	missense_variant	7/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.697C>T	p.Pro233Ser	missense_variant	8/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.514C>T	p.Pro172Ser	missense_variant	3/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461570 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727086

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2020	PS4_Moderate, PM2, PM5, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); At the protein level, silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 67130; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 22581653, 23392653, 19540844, 26669661, 29033053, 27041150, 32383558) -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the KCNQ1 protein (p.Pro320Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 23392653; Invitae). ClinVar contains an entry for this variant (Variation ID: 67130). 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%. This variant disrupts the p.Pro320 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19540844, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2022	Variant summary: KCNQ1 c.958C>T (p.Pro320Ser) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 253994 control chromosomes. c.958C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Three 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 29, 2022

_x000D_ Criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3 -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2019

The p.P320S variant (also known as c.958C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 958. The proline at codon 320 is replaced by serine, an amino acid with similar properties, and is located in the pore domain. This variant was detected in an individual with prolonged QT, who also had an additional KCNQ1 variant detected, as well as in her affected son who had prolonged QT and only this variant (Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200). In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data, Sun J et al. Cell, 2017 Jun;169:1042-1050.e9). Alternate amino acid substitutions at this codon, p.P320A and p.P320H, have also been reported in LQTS cohorts, and functional studies supported a dominant negative impact for both variants (Donger C et al. Circulation, 1997 Nov;96:2778-81; Thomas D et al. J. Mol. Cell. Cardiol., 2010 Jan;48:230-7). 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. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

-

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.Pro320Ser Given the weak case data and minimal controls, we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in at least one unrelated cases of long QT syndrome (not including this patient's family), possibly two. There is weak segregation data. The variant was reported in one individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Ancestry was not provided. Ackerman's group later reported a patient seen in their Mayo LQTS clinic who was a compound heterozygote for this variant and p.Pro448Leu (Giudicessi et al 2013). The patient was a female with a QTc of 499 ms, one syncopal episode, and normal hearing. Several family members who carry just p.Pro448Leu had normal QTc measurements while the proband's son carried just p.Pro320Ser and had a QTc of 505 ms. Ancestry was not provided. That case may overlap with Kapplinger et al (2009) as some of the patients had commercial genetic testing. Unfortunately insufficient information is provided in Kapplinger et al (2009) to determine if it is in fact the same case. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 1.000). The proline at codon 320 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Pro320Ala, p.Pro320His) and nearby codons (p.Val310Asn, p.Val310Ile, p.Gly314Asn, p.Gly314Arg, p.Gly314Ser, p.Gly316Glu, p.Gly316Arg, p.Gly316Val, p.Gly316Val, p.Lys318Asn, p.Thr322Ala, p.Thr322Lys, p.Thr322Met, p.Gly325Arg, p.Gly325Glu, p.Gly325Trp). In total the variant has not been seen in ~9800 published controls and individuals from publicly available population datasets. There is no variation at codon 320 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 8th, 2014). The variant is listed in dbSNP (rs199472753), however the only submission is a locus specific database noting reports with disease in the literature. The variant was not observed in the following published control samples: 1300 ostensibly healthy individuals (Kapplinger et al 2009). -

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: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	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.5	D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.95		Loss of methylation at K318 (P = 0.075);.;.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		1.0

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: rs199472753; hg19: chr11-2604701;