rs199473545

chr7-150946929-G-Achr7-150946929-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000238.4(KCNH2):c.3278C>T(p.Pro1093Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,602,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1093P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 2.87

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 10 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3278C>T	p.Pro1093Leu	missense_variant	14/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3278C>T	p.Pro1093Leu	missense_variant	14/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2258C>T	p.Pro753Leu	missense_variant	10/11	1
KCNH2	ENST00000684241.1	n.4111C>T		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000329 AC: 8 AN: 243530 Hom.: 0 AF XY: 0.0000381 AC XY: 5 AN XY: 131306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000592

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: 0.0000455

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1449974 Hom.: 0 Cov.: 32 AF XY: 0.0000111 AC XY: 8 AN XY: 719518

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000683

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000724

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 13, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Pro1093Leu Based on the data reviewed below we consider it a variant of uncertain significance. There is also a possibility that it is a modifier and not the primary driver of disease. The variant has been seen in at least 1 case of long QT syndrome. The variant was reported in two individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group. Of note in considering the other case reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen in isolated and which were seen with another variant (9% of the cohort had multiple variants). In a presentation online by Kimura et al they note that they observed the variant in a patient with Anderson-Tawil syndrome, who also carried p.Arg82Trp in KCNJ2 (Anderson-Tawil is caused by pathogenic variants in KCNJ2). In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts it to be tolerated. The proline at codon 1093 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon and nearby codons. However, nearby variants suspected to be benign have been reported (p.Ser1092Phe, p.Val1097Ile). The variant is in the c-terminal region of the protein. Kapa et al (2012) report that variants in this region have a 73% likelihood of being associated with long QT syndrome (vs. 100% in the transmembrane region). In total the variant has not been seen in ~ 7800 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 1093 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of December 31st, 2013). The variant is listed in dbSNP but only in reference to the long QT associated data reviewed above (rs199473545). The variant was not observed in the following laboratory and published control samples: 1300 presumed health individuals of varying ethnicities studied by Kapplinger et al (2009). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 probands, 1 functional study suggests benign -

Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 26, 2019

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1093 of the KCNH2 protein (p.Pro1093Leu). This variant is present in population databases (rs199473545, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 22949429, 29727688). ClinVar contains an entry for this variant (Variation ID: 67485). 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 tolerated. 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. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 08, 2021

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 04, 2018

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual with arrhythmia (PMID: 28567303), in an individual with a family history of sudden cardiac death (PMID: 21499742) and in an individual affected with typical Andersen-Tawil syndrome, who also carried a variant in the KCNJ2 gene (PMID: 22589293). This variant has also been identified in 9/238484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -

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;PMID:19841300). 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	0.078
CardioboostArm	Benign	0.000059
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.054	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.14	B;B
Vest4		0.41
MVP		0.98
MPC		0.18
ClinPred		0.17	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.29

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: rs199473545; hg19: chr7-150644017;