rs199473431

Variant names:

• chr7-150951631-T-C
• rs199473431
• NM_000238.4:c.1762A>G

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.1762A>G​(p.Asn588Asp) variant causes a missense change involving the alteration of a non-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: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 0.329

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 helix (size 7) in uniprot entity KCNH2_HUMAN there are 5 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, 0.969
• PP5: Variant 7-150951631-T-C is Pathogenic according to our data. Variant chr7-150951631-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67266.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr7-150951631-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1762A>G	p.Asn588Asp	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1762A>G	p.Asn588Asp	missense_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

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

Aug 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the N588D variant, located in the extracellular domain, causes deficient protein trafficking in the cell membrane that is correctable at lower temperatures (Anderson et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 22949429, 9693036, 25417810, 15840476) -

Long QT syndrome Uncertain:1

Dec 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with long QT syndrome (PMID: 22949429). ClinVar contains an entry for this variant (Variation ID: 67266). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). 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 is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 588 of the KCNH2 protein (p.Asn588Asp). -

Congenital long QT syndrome Other:1

-

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:9693036;PMID:15840476;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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	.;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Uncertain	0.62
Sift	Benign	0.095	T;T;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.014	B;B;.
Vest4		0.73
MutPred		0.88		.;Gain of disorder (P = 0.1627);.;
MVP		0.93
MPC		2.1
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.29
gMVP		0.90

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: rs199473431; hg19: chr7-150648719;