rs199473433

Positions:

• chr7-150948456-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BS2_Supporting

The NM_000238.4(KCNH2):​c.2680C>T​(p.Arg894Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,834 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R894H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 2.05

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000238.4
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 7 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2680C>T	p.Arg894Cys	missense_variant	11/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2680C>T	p.Arg894Cys	missense_variant	11/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1660C>T	p.Arg554Cys	missense_variant	7/11	1
KCNH2	ENST00000684241.1	n.3513C>T		non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244528 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133006

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1452834 Hom.: 0 Cov.: 37 AF XY: 0.00000415 AC XY: 3 AN XY: 723174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	KCNH2: PM5, PM2:Supporting, PP2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	The R894C variant of uncertain significance in the KCNH2 gene has been reported in one individual referred for LQTS testing (Kapplinger et al., 2009). Wang et al. (2014) identified R894C in a 38 year-old woman with sudden unexplained death and negative autopsy. The R894C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R894C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, a majority of splice-prediction algorithms predict that R894C creates a new cryptic splice donor site located upstream of natural splice donor site in intron 7; however, the new upstream donor site is predicted to be weaker than natural site. Lastly, a variant at this same residue (R894L) has been reported in HGMD in association with LQTS (Stenson et al., 2014), although the clinical significance of this variant has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Long QT syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2019	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with LQTS (Invitae), LQTS and congenital heart malformations (PMID: 28532774), sudden unexpected death (PMID: 24631775), and in an individual referred for LQTS genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67424). This variant is present in population databases (rs199473433, ExAC 0.002%). This sequence change replaces arginine with cysteine at codon 894 of the KCNH2 protein (p.Arg894Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 27, 2023	This missense variant replaces arginine with cysteine at codon 894 of the KCNH2 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 28532774, ClinVar SCV000935380.5), in an individual suspected of having long QT syndrome (PMID: 19716085), and in an individual affected with sudden unexplained death (PMID: 24631775). This variant has been identified in 2/244528 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2023

The p.R894C variant (also known as c.2680C>T), located in coding exon 11 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2680. The arginine at codon 894 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in long QT syndrome cohorts and a sudden unexplained death cohort; however clinical details were limited in some cases (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Wang D et al. Forensic Sci Int, 2014 Apr;237:90-9; Ebrahim MA et al. Am J Cardiol, 2017 Jul;120:256-261). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	35
DANN	Pathogenic	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.99	D;D
Vest4		0.65
MutPred		0.80		.;Loss of MoRF binding (P = 0.038);
MVP		1.0
MPC		0.62
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.17
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473433; hg19: chr7-150645544;