rs375872367

Positions:

• chr7-150951790-C-A
• chr7-150951790-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000238.4(KCNH2):​c.1603G>T​(p.Val535Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,896 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: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 20) in uniprot entity KCNH2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1603G>T	p.Val535Leu	missense_variant	7/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1603G>T	p.Val535Leu	missense_variant	7/15	1	NM_000238.4	ENSP00000262186	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440896 Hom.: 0 Cov.: 36 AF XY: 0.00000140 AC XY: 1 AN XY: 713294

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2018

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 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KCNH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 535 of the KCNH2 protein (p.Val535Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;.
Sift4G	Benign	0.22	T;T;T
Polyphen		0.11	B;P;.
Vest4		0.78
MutPred		0.54		.;Loss of methylation at K538 (P = 0.0947);.;
MVP		0.96
MPC		2.2
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.96

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: rs375872367; hg19: chr7-150648878;