rs199472888

chr7-150957418-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000238.4(KCNH2):c.1001C>T(p.Pro334Leu) 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. P334S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 9.94

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 7-150957418-G-A is Pathogenic according to our data. Variant chr7-150957418-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67161.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Pathogenic=1}. Variant chr7-150957418-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1001C>T	p.Pro334Leu	missense_variant	5/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1001C>T	p.Pro334Leu	missense_variant	5/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1224C>T		non_coding_transcript_exon_variant	5/9	2
KCNH2	ENST00000684241.1	n.1834C>T		non_coding_transcript_exon_variant	3/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 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 15, 2014

p.Pro334Leu (CCC>CTC): c.1001 C>T in exon 5 of the KCNH2 gene (NM_000238.2). The P334L variant in the KCNH2 gene has been reported in association with LQTS (Lupoglazoff et al., 2001; Imboden et al., 2006). The P334L was identified as a novel mutation in 1 out of 57 affected individual with LQTS, and was absent from 150 control chromosomes (Lupoglazoff et al., 2001). Additionally, of the 240 families of European ancestry with LQTS studied by Imoboden et al., 2006, one family was reported to harbor the P334L mutation. The P334L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R328C, D342V) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Furthermore, the P334L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, P334L in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2021

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 334 of the KCNH2 protein (p.Pro334Leu). 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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67161). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 11222472, 17088455, 32383558; Invitae). This variant is not present in population databases (gnomAD no frequency). -

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:11222472). 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	0.99
CardioboostArm	Uncertain	0.30
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.017	D;D
Polyphen		0.97	D;.
Vest4		0.80
MutPred		0.82		Gain of MoRF binding (P = 0.048);.;
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.79

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: rs199472888; hg19: chr7-150654506;