7-150974931-G-T

Variant names:

• chr7-150974931-G-T
• rs199472830
• NM_000238.4:c.87C>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.87C>A​(p.Phe29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.28

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 7-150974931-G-T is Pathogenic according to our data. Variant chr7-150974931-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 67538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150974931-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.87C>A	p.Phe29Leu	missense_variant	Exon 2 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.87C>A	p.Phe29Leu	missense_variant	Exon 2 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.310C>A		non_coding_transcript_exon_variant	Exon 2 of 9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452354 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 722062

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: 0.0000205

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

May 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine with leucine at codon 29 of the KCNH2 protein (p.Phe29Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNH2 protein function (PMID: 26403377, 22396785, 25417810, 21536673, 23721480, 10187793, 30988392). This variant has been observed in several individuals with long QT syndrome (LQTS) and observed to segregate with LQTS in a family (PMID: 17088455, 26403377). ClinVar contains an entry for this variant (Variation ID: 67538). -

Jan 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.87C>A (p.Phe29Leu) variant in KCNH2 gene, that encodes for potassium voltage-gated channel subfamily H member 2, has been identified in multiple unrelated probands (>10) with Long QT syndrome (PMID: 26403377, 29343803, 28235848, 32893267). This variant has been identified as a founder variant in thirty-three members of five apparently unrelated Danish families with congenital long QT syndrome (PMID:26403377). This variant has also been reported in one individual with sudden cardiac death (PMID: 31729605). Several functional studies using transfected HEK cells and Xenopus laevis oocytes revealed a loss-of-function phenotype with trafficking defects, accelerated deactivation of functional channels, altered channel gating, reduced steady-state inactivation current density and a positive voltage shift in inactivation, compared to wild type (PMID: 26403377, 10187793, 21536673, 31557540, 30988392, 22396785). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.843). This variant is absent in the general population database, gnomAD and interpreted as pathogenic in ClinVar (ClinVar ID: 67538). Therefore, the c.87C>A (p.Phe29Leu) variant in the KCNH2 gene is classified as pathogenic. -

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:10187793;PMID:10973849;PMID:11668638;PMID:11854117;PMID:15840476;PMID:15851171;PMID:16937190;PMID:19716085;PMID:21536673;PMID:22396785). 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	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.027
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0	B
Vest4		0.96
MutPred		0.82		Loss of methylation at K28 (P = 0.035);
MVP		1.0
MPC		1.2
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.85
gMVP		0.99

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: rs199472830; hg19: chr7-150672019;