rs199473421

Positions:

• chr7-150974803-G-A
• chr7-150974803-G-C
• chr7-150974803-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.215C>T​(p.Pro72Leu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.88

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150974803-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-150974803-G-A is Pathogenic according to our data. Variant chr7-150974803-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67370.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.215C>T	p.Pro72Leu	missense_variant	2/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.215C>T	p.Pro72Leu	missense_variant	2/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.438C>T		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452478 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 721970

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2019

Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate deficient protein trafficking (Anderson et al., 2014); Different missense variants in the same residue (P72Q, P72T, P72R) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19716085, 25417810, 32475984) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2018

The p.P72L variant (also known as c.215C>T), located in coding exon 2 of the KCNH2 gene, results from a C to T substitution at nucleotide position 215. The proline at codon 72 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in several individuals with long QT syndrome (Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Migdalovich D et al. Heart Rhythm. 2011;8:1537-43; Itoh H et al. Eur. J. Hum. Genet. 2016;24:1160-6; GeneDx pers. comm.). Functional studies have demonstrated that this alteration causes a trafficking defect in mammalian cells (Anderson CL et al. Nat Commun. 2014;5:5535; Perry MD et al. J. Physiol. (Lond.). 2016;594:4031-49). Two likely pathogenic variants, p.P72Q and p.P72R, have been described in the same codon (Splawski I et al. Circulation. 2000;102:1178-85; Crotti L et al. Hum. Genet. 2008;123:537-55). This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other 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. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2022

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. This variant disrupts the p.Pro72 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 25417810; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810, 32475984). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67370). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19716085). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the KCNH2 protein (p.Pro72Leu). -

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). 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.86		Gain of catalytic residue at P72 (P = 0.0042);.;
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.88
gMVP		0.96

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: rs199473421; hg19: chr7-150671891;