rs199472988

Positions:

• chr7-150950362-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000238.4(KCNH2):​c.2204C>T​(p.Ser735Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 1.27

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2204C>T	p.Ser735Leu	missense_variant	9/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2204C>T	p.Ser735Leu	missense_variant	9/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249096 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135258

Gnomad AFR exome AF: 0.00

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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460672 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726672

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2015	Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change may affect normal protein trafficking (PMID: 25417810), but the clinical significance of the this observation is uncertain. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant has been reported in the literature and is present in population databases (rs199472988, <0.01%). It was reported in an newborn with bradycardia, and was observed in the newborn's clinically unaffected father (PMID: 16379539). This sequence change replaces serine with leucine at codon 735 of the KCNH2 protein (p.Ser735Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 24, 2023	This missense variant replaces serine with leucine at codon 735 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). In vitro functional studies in HEK293 cells suggest that this variant may impact protein trafficking (PMID: 25417810), however the clinical relevance of this observation is unknown. This variant has been reported in an infant with suspected long QT syndrome (PMID: 16379539). This variant has been identified in 1/249096 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2020

Identified in a newborn with bradycardia but a normal QT interval on EKG and in the newborn's clinically unaffected father (Shim et al., 2005); Identified in conjunction with additional cardiogenetic variants in unrelated individuals referred for arrhythmia genetic testing at GeneDx, but segregation data is limited at this time; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Published functional studies in HEK293 cells demonstrate this variant may affect normal protein trafficking (Anderson et al., 2014). However, the clinical validity of these studies remains to be determined, and further functional evidence is needed to clarify the role of this variant in human disease.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67374; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16379539, 22581653, 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:16379539). 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	0.27
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.92	.;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.62
Sift	Benign	0.076	T;D;.
Sift4G	Benign	0.093	T;T;T
Polyphen		0.011	B;B;.
Vest4		0.58
MutPred		0.40		.;Gain of helix (P = 0.132);.;
MVP		0.97
MPC		1.2
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199472988; hg19: chr7-150647450; COSMIC: COSV51129996;