rs199473505

chr7-150957437-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000238.4(KCNH2):c.982C>T(p.Arg328Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,614,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign 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. R328H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8 O:1
• Conservation: PhyloP100: 3.28

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0545232).
• BS2: High AC in GnomAd at 93 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.982C>T	p.Arg328Cys	missense_variant	5/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.982C>T	p.Arg328Cys	missense_variant	5/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1205C>T		non_coding_transcript_exon_variant	5/9	2
KCNH2	ENST00000684241.1	n.1815C>T		non_coding_transcript_exon_variant	3/13

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000570 AC: 143 AN: 250832 Hom.: 0 AF XY: 0.000560 AC XY: 76 AN XY: 135796

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000417 AC: 609 AN: 1461806 Hom.: 3 Cov.: 32 AF XY: 0.000388 AC XY: 282 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00412

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000610 AC: 93 AN: 152382 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74512

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2 Other:1

Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 15, 2016	Given the weak case data and presence in population controls, we consider this variant likely benign. One possibility is that this variant contributes to an arrhythmic phenotype, perhaps behaving as a modifier, but not be the primary driver. This is based on the fact that several of the reported cases involved either a more convincing pathogenic variant or QT-prolonging medication, several other reported cases are from cohorts that include individuals who do not have long QT, and the variant is present in individuals not selected for a long QT phenotype, with ~1% of one such cohort having the variant. This is a previously reported variant in the N-terminal region. To date, the reported cases include - drug-induced long QT, complete AV block and Torsades: 2 - patients referred for long QT genetic testing, 25-50% likely don't have long QT: 6 - patients with long QT, all major genes analyzed with no other variants: 4 - patients with long QT and another, high confidence variant: 1 - patient with prolonged QT in the setting of evidence of arrhythmogenic right ventricular cardiomyopathy and a PKP2 frameshift variant: 1 Comparing frequencies: - 4/2500 in Kapplinger series (0.16%) - 64/60,618 in ExAC (0.11%) - 38/3189 Finnish in ExAC (1.2%) -162/141,162 in gnomAD (0.11%); -115/13031 Finnish in gnomAD (0.88%) Chevalier et al (2001) reported the variant in association with what the authors described as acquired long QT syndrome. They found the variant in 1 of 16 cases. The individual with the variant was a 45yo male with no prior medical history of family history of sudden death. He was hospitalized for recent syncopal episodes. An ECG at admission showed QT prolongation and complete AV block, he was diagnosed with "Torsades de pointes" complicating an AV bock and a pacemaker was placed and the QT interval returned to normal once he was paced. Tester et al (2005) observed the variant in 2 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). Millat et al (2006) reported the variant in 3 of 44 unrelated individuals from their French cohort with long QT syndrome with QTc intervals ranging from 483 to 540 ms. No segregation data was provided. They analyzed 5 long QT genes. Hinterseer et al (2006) reported the variant in a 25yo woman who suffered Torsades de Pointes in the setting of transiently impaired LV function, acute respiratory distress syndrome, transient hypokalaemia and QT-prolonging drugs, with a QTc of 485-510 ms. Once her status had normalized and QT-prolonging drugs had been discontinued her QTc was 430 ms and a Dl-sotalol challenge evoked a QTc of 515 ms, which the authors felt was suggestive of a latent susceptibility to QT-prolonging drugs. Four other family members were found to have the variant, "all without clinical manifestations of LQTS". The variant was reported in 4 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. 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). Stattin et al (2012) analyzed 5 long QT genes in 200 unrelated long QT patients from their Swedish cohort and identified this variant in one individual. Hedley et al (2013) report -
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:11334843;PMID:14760488;PMID:15840476;PMID:16253915;PMID:16432067;PMID:16720674;PMID:16922724;PMID:17275752;PMID:19716085;PMID:19841300). -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	KCNH2: PP2, BS1 -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2017	The R328C variant in the KCNH2 gene has been previously reported in multiple unrelated individuals with LQTS and was absent in >2,600 reference alleles, when considering all published studies (Tisma-Dupanovic et al., 2013; Kapplinger et al., 2009; Tester et al., 2005; Chevalier et al., 2001). The R328C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however, the 1000 Genomes Project observed this variant at low frequency in 2/198 Finnish alleles and in 2/208 Puerto Rican alleles. One previously asymptomatic individual identified to have the R328C variant developed Torsades de Pointes in the context of respiratory distress, left ventricular dysfunction, and a prolonged QT interval while being treated with multiple medications (Hinterseer et al., 2006). Several relatives who were also found to harbor this variant, including the patient's identical twin, had no clinical evidence of LQTS, leading authors to conclude this patient's arrhythmia likely resulted from multiple factors. Chevalier et al. (2001) reported R328C leads to a partial dominant-negative effect and alters KCNH2 channel function; however, subsequent functional studies found that the channel function of R328C-KCNH2 did not differ significantly from the wild type KCNH2 channel function (Grunnet et al., 2005; Anderson et al., 2006). Nevertheless, R328C is a non-conservative amino acid substitution occurring at a position that is conserved across species. Multiple missense variants in nearby residues (S320W, S320L, D323N, P334L) have been reported in Human Genome Mutation Database in association with LQTS (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Long QT syndrome Benign:2

Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Dec 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2020

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. -

KCNH2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
CardioboostArm	Benign	0.091
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.99
MPC		2.4
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.20
gMVP		0.77

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: rs199473505; hg19: chr7-150654525; COSMIC: COSV51170714; COSMIC: COSV51170714;