rs121912512

chr7-150950311-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000238.4(KCNH2):c.2255G>A(p.Arg752Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R752W) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 30)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 O:1
• Conservation: PhyloP100: 7.90

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150950312-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 67379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 7-150950311-C-T is Pathogenic according to our data. Variant chr7-150950311-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2255G>A	p.Arg752Gln	missense_variant	9/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2255G>A	p.Arg752Gln	missense_variant	9/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250528 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135648

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 38

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.0000482

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000534 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Aug 31, 2023	The KCNH2 c.2255G>A (p.Arg752Gln) variant has been reported in two individuals affected with Long QT syndrome, one heterozygote (Choi SH et al., PMID: 34319147) and one homozygote (Johnson WH et al., PMID: 12621127). Johnson and colleagues make note that three family members to the homozygous patient were heterozygous for the p.Arg752Gln variant and were asymptomatic (Johnson WH et al., PMID: 12621127). The variant is only observed on 2 alleles out of 281,892 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Functional studies show that this variant leads to significantly decreased channel function and disrupts protein trafficking (Anderson CL et al., PMID: 25417810; Johnson WH et al., PMID: 12621127). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNH2 function. Another variant in the same codon, c.2254C>T (p.Arg752Trp), has been reported in affected individuals with Long QT and is considered pathogenic (Ficker E et al., PMID: 11009462; Itoh H et al., PMID: 26669661; Nagaoka I et al., PMID: 18441445; Splawski I et al., PMID: 10973849; Stattin EL et al., PMID: 23098067, ClinVar Variation ID: 67379). This variant has been reported in the ClinVar database as a pathogenic variant, a likely pathogenic variant, and a variant of uncertain significance by one submitter each in association for Long QT syndrome. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -

Long QT syndrome Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 752 of the KCNH2 protein (p.Arg752Gln). This variant is present in population databases (rs121912512, gnomAD 0.008%). This missense change has been observed in individuals with long QT interval (PMID: 12621127, 34319147; Invitae). ClinVar contains an entry for this variant (Variation ID: 14435). 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: 12621127, 25417810). This variant disrupts the p.Arg752 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 11009462, 18441445). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2021

Reported as a homozygous variant in a patient with Long QT syndrome diagnosed in utero; however, heterozygous family members had normal QT intervals (Johnson et al., 2003); Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 14435; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant leads to significantly decreased channel function and causes a protein trafficking defect (Johnson et al., 2003; Anderson et al., 2014); This variant is associated with the following publications: (PMID: 12621127, 25637381, 25417810) -

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:12621127). 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	0.98
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.59
gMVP		0.84

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: rs121912512; hg19: chr7-150647399; COSMIC: COSV51137157;