rs199472883

Positions:

• chr7-150958073-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000238.4(KCNH2):​c.902G>T​(p.Arg301Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,120,784 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: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.583

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.902G>T	p.Arg301Leu	missense_variant	4/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.902G>T	p.Arg301Leu	missense_variant	4/15	1	NM_000238.4	ENSP00000262186	P1
KCNH2	ENST00000532957.5	n.1125G>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1735G>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000268 AC: 3 AN: 1120784 Hom.: 0 Cov.: 31 AF XY: 0.00000375 AC XY: 2 AN XY: 533118

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: 0.0000342

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000106

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other: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

Nov 24, 2021

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 301 of the KCNH2 protein (p.Arg301Leu). This variant is not present in population databases (gnomAD no frequency). 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67542). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085). -

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	Benign	0.30
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.68
Sift	Benign	0.034	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.98	D;.
Vest4		0.58
MutPred		0.75		Loss of solvent accessibility (P = 0.0052);.;
MVP		1.0
MPC		1.2
ClinPred		0.96	D
GERP RS		3.4
Varity_R		0.32
gMVP		0.66

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: rs199472883; hg19: chr7-150655161;