NM_000238.4:c.1881C>A

Variant names:

• chr7-150951512-G-T
• rs199473039
• NM_000238.4:c.1881C>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1881C>A​(p.Phe627Leu) 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F627I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.14
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS1: Transcript NM_000238.4 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-150951512-G-T is Pathogenic according to our data. Variant chr7-150951512-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 200747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1881C>A	p.Phe627Leu	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.1881C>A	p.Phe627Leu	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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 16, 2011

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe627Leu mutation in the KCNH2 gene has been published previously in association with LQTS (1-3). Phe627Leu, located in the pore region of the protein, has been reported in individuals with LQTS who harbored a different nucleotide substitution which resulted in the same Phe627Leu protein change as this patient (c.1879 T>C and c.1881 C>G, respectively). Lin et al. (2008) reported a 25-week fetus with intermittent AV block due to an extremely long QT interval who harbored the Phe627Leu mutation in the KCNH2 gene, as well as a missense mutation in the SCN5A gene. Another mutation affecting the same residue (Phe627Ile) as well as neighboring residues (Val625Glu, Gly626Ala, Gly626Asp, Gly626Ser, Gly626Val, Gly628Ala, Gly628Ser, Gly628Val) have also been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. Phe627Leu was not detected in over 400 control chromosomes reported in the literature, nor in up to 400 control chromosomes of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphism in these populations. Therefore, the presence of the Phe627Leu mutation in the KCNH2 gene is consistent with a diagnosis of an autosomal dominant form of LQTS. The variant is found in LQT panel(s). -

Long QT syndrome Pathogenic:1

Apr 22, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 24322056, 24217263, 18848812, 11854117). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200747). This missense change has been reported to affect KCNH2 protein function (PMID: 25417810, 18848812). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 627 of the KCNH2 protein (p.Phe627Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Benign	-0.79
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.34	N
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.
PhyloP100		-2.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D;D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.97
MutPred		0.92		.;Loss of helix (P = 0.079);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473039; hg19: chr7-150648600;