7-150951097-C-T

Variant names:

• chr7-150951097-C-T
• rs199472978
• NM_000238.4:c.1969G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.1969G>A​(p.Gly657Ser) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 7.86

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S6 (size 20) in uniprot entity KCNH2_HUMAN there are 9 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, 0.953
• PP5: Variant 7-150951097-C-T is Pathogenic according to our data. Variant chr7-150951097-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67348.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1969G>A	p.Gly657Ser	missense_variant	Exon 8 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1969G>A	p.Gly657Ser	missense_variant	Exon 8 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital long QT syndrome Pathogenic:1 Other:1

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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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. -

Jun 07, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly657Ser variant in KCNH2 has been previously reported in 1 individual referred for long QT syndrome (LQTS) genetic testing, and it has also been observed in 3 individuals with a reported diagnosis of LQTS by a clinical testing laboratory (Kapplinger 2009, personal communication ClinVar SCV000261846.3). It was absent from large population studies. In vitro functional studies have demonstrated an impact to normal KCNH2 potassium channel function, including when the variant is co-expressed with wild-type (Perry 2016, Hardman 2007). This variant is located in the transmembrane spanning S5/pore region of the KCNH2 protein, which has been deemed important for proper channel function (Kapa 2009 PMID: 19841300).Computational prediction tools and conservation analyses suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PM2_Supporting, PP3, PM1, PS3_Supporting, PS4_Supporting. -

not provided Pathogenic:1

Aug 12, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with suspected long QT syndrome (Marschall et al., 2019); Published functional studies demonstrate a damaging effect, including defective protein expression, reduced charge during repolarization, reduced IKv11.1 amplitude in response to premature depolarization, and slower deactivation kinetics (Perry et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 17823114, 20393304, 25348405, 19716085, 20850565, 26958806, 31737537) -

Long QT syndrome Pathogenic:1

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Gly657Cys amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18752142, 18955593, 19862833, 26675252). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 17823114, 19841300, 25348405, 26958806). 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. ClinVar contains an entry for this variant (Variation ID: 67348). This missense change has been observed in individuals with KCNH2-related conditions (PMID: 19716085; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 657 of the KCNH2 protein (p.Gly657Ser). -

Cardiovascular phenotype Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G657S variant (also known as c.1969G>A), located in coding exon 8 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1969. The glycine at codon 657 is replaced by serine, an amino acid with similar properties. This alteration has been reported in long QT syndrome cohorts; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Berge KE et al. Scand J Clin Lab Invest, 2008;68:362-8; Kim JA et al. Heart Rhythm, 2010 Dec;7:1797-805; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Additionally, an in vitro study showed this alteration impacts protein function (Perry MD et al. J Physiol, 2016 Jul;594:4031-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.92
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199472978; hg19: chr7-150648185; COSMIC: COSV51130527;