rs141401803

Variant names:

• chr7-150947711-G-A
• rs141401803
• NM_000238.4:c.2860C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BS2_Supporting

The NM_000238.4(KCNH2):​c.2860C>T​(p.Arg954Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 1,580,214 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 1.38

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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• BS2: High AC in GnomAd4 at 6 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 rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2860C>T	p.Arg954Cys	missense_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2860C>T	p.Arg954Cys	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1840C>T	p.Arg614Cys	missense_variant	Exon 8 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3693C>T		non_coding_transcript_exon_variant	Exon 10 of 13

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000375 AC: 7 AN: 186632 Hom.: 0 AF XY: 0.0000390 AC XY: 4 AN XY: 102580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000476 AC: 68 AN: 1428058 Hom.: 0 Cov.: 36 AF XY: 0.0000410 AC XY: 29 AN XY: 708030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000484

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000556

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000255 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 954 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown this variant may reduce ionic current and accelerate channel deactivation (PMID: 17210839, 18222468, 18675227). This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839), drug-induced QT prolongation (PMID: 18675227), atrial fibrillation (Han et al., 2010), sudden unexplained death (PMID: 27930701), and sudden death suspected of being an inherited arrhythmogenic syndrome (PMID: 32268277). This variant has also been identified in 8/217960 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. -

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 954 of the KCNH2 protein (p.Arg954Cys). This variant is present in population databases (rs141401803, gnomAD 0.005%). This missense change has been observed in individuals with KCNH2-related conditions and/or Long QT (PMID: 17210839, 18675227, 27930701; Invitae). ClinVar contains an entry for this variant (Variation ID: 67444). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 17210839, 18222468, 18675227). This variant disrupts the p.Arg954 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 27026747), which suggests that this may be a clinically significant amino acid residue. 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. -

not specified Uncertain:1

Jul 17, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.2860C>T (p.Arg954Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 186996 control chromosomes. c.2860C>T has been reported in the literature in individuals affected with clinical features of KCNH2-related conditions, including SIDS (e.g., Arnestad_2007) and drug-induced arrhythmia and/or prolonged QT (e.g, Biliczki_2008, Behr_2013). These data indicate that the variant may be associated with disease. At least two publications suggest the variant inhibits biophyisical properties (e.g., Biliczki_2008, Rhodes_2008). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 18222468, 18675227, 24223155). ClinVar contains an entry for this variant (Variation ID: 67444). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Mar 31, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with sudden infant death syndrome (SIDS) or sudden unexpected death (SUD) (Arnestad et al., 2007; Sanchez et al., 2016); Also reported in an individual with an increased QTc interval during macrolide treatment that normalized after drug withdrawal, as well as in her daughter who had a QTc of approximately 450ms (Biliczki et al., 2008); Published functional studies demonstrate a damaging effect as this variant results in reduced channel current and significant alterations in channel biophysical properties (Rhodes et al., 2008; Biliczki et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21778721, 23304551, 24223155, 21215473, 28316956, 26633542, 27026747, 18675227, 27930701, 34502138, 22581653, 32048431, 32268277, 17210839, 31043699, 18222468) -

Cardiovascular phenotype Uncertain:1

Jun 04, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2860C>T (p.R954C) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2860, causing the arginine (R) at amino acid position 954 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Apr 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 954 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown this variant may reduce ionic current and accelerate channel deactivation (PMID: 17210839, 18222468, 18675227). This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839), drug-induced QT prolongation (PMID: 18675227), atrial fibrillation (Han et al., 2010), sudden unexplained death (PMID: 27930701), and sudden death suspected of being an inherited arrhythmogenic syndrome (PMID: 32268277). This variant has also been identified in 8/217960 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. -

SUDDEN INFANT DEATH SYNDROME Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:17210839;PMID:18675227). 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	0.11
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.69	.;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.5	N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.10	T;T
Polyphen		1.0	D;D
Vest4		0.60
MVP		0.99
MPC		0.62
ClinPred		0.22	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.18
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs141401803; hg19: chr7-150644799;