7-150949034-A-G

Variant names:

• chr7-150949034-A-G
• rs199472999
• NM_000238.4:c.2414T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000238.4(KCNH2):​c.2414T>C​(p.Phe805Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F805C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150949034-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 7-150949034-A-G is Pathogenic according to our data. Variant chr7-150949034-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 67396.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150949034-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2414T>C	p.Phe805Ser	missense_variant	Exon 10 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2414T>C	p.Phe805Ser	missense_variant	Exon 10 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1394T>C	p.Phe465Ser	missense_variant	Exon 6 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3247T>C		non_coding_transcript_exon_variant	Exon 8 of 13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 02, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe805Ser mutation in the KCNH2 gene has been reported previously in one individual with a diagnosis of LQTS and it was absent from more than 400 control alleles. Additionally, the NHLBI ESP Exome Variant Server reports Phe805Ser was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Phe805Ser results in a non-conservative amino acid substitution of a non-polar Phenylalanine residue with a polar Serine residue. Other mutations in this codon (Phe805Cys) and in nearby codons (Gly800Glu, Gly800Trp, Gly806Glu) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. Therefore, the presence of the Phe805Ser mutation in the KCNH2 gene is consistent with a diagnosis of LQTS. The variant is found in LQT panel(s). -

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:10973849). 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	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.93	P;D
Vest4		1.0
MutPred		0.95		.;Gain of disorder (P = 0.0085);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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: rs199472999; hg19: chr7-150646122;