rs199473527

Positions:

• chr7-150951499-G-A
• chr7-150951499-G-C
• chr7-150951499-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1894C>T​(p.Pro632Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.85

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]

KCNH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNH2_HUMAN there are 23 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, 0.987
• PP5: Variant 7-150951499-G-A is Pathogenic according to our data. Variant chr7-150951499-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951499-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1894C>T	p.Pro632Ser	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.1894C>T	p.Pro632Ser	missense_variant	7/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2014	p.Pro632Ser (CCC>TCC): c.1894 C>T in exon 7 of the KCNH2 gene (NM_000238.2). The P632S mutation in the KCNH2 gene has been reported in one individual with LQTS and it was absent from more than 400 control chromosomes (Splawski I et al., 2000). Furthermore, the P632S mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, P632S results in 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, at a position that is conserved across mammalian species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, a mutation in this residue (P632A) and mutations in nearby residues (S631A, N633D, N633I, N633S, N633K) have been reported in association with LQTS, further supporting the functional importance of this residue andregion of the protein. In summary, P632S in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 13, 2021	PS3, PS4_supporting, PM1, PM2, PP3 -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2019

The p.P632S variant (also known as c.1894C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1894. The proline at codon 632 is replaced by serine, an amino acid with similar properties. This variant was reported in two studies of individuals and families reported to have long QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Andrsova I et al. J Electrocardiol. 2012;45(6):746-51). One study with in vitro analyses suggested this alteration to result in abnormal protein trafficking (Anderson CL et al. Nat Commun. 2014;5:5535). In addition, another alteration affecting the same amino acid (p.P632A (c.1894C>G)) has also been reported in association with LQTS (Mullally J et al. Heart Rhythm. 2013;10(3):378-82). This variant was previously reported in the SNPDatabase as rs199473527. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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:10973849). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.8	D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0080	D;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.94
MutPred		0.90		.;Gain of disorder (P = 0.0619);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.73
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473527; hg19: chr7-150648587; COSMIC: COSV51217661;