7-150974807-C-G

Position:

• chr7-150974807-C-G

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.211G>C​(p.Gly71Arg) 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 (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 2.67

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 (HGNC:):

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, 0.96
• PP5: Variant 7-150974807-C-G is Pathogenic according to our data. Variant chr7-150974807-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 67366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150974807-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.211G>C	p.Gly71Arg	missense_variant	2/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.211G>C	p.Gly71Arg	missense_variant	2/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.434G>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2012

Gly71Arg has been reported previously in two unrelated patients referred for LQTS testing and itwas absent in 800 reference alleles (Napolitano C et al., 2005; Itoh H et al., 2010). Additionally, the NHLBI ESP Exome Variant Server reports Gly71Arg was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Gly71Arg leads to a non-conservative replacement of a non-polar small Glycine residue with a large polar Arginine residue in the N-terminus of the protein. In addition, other missense mutations affecting neighboring codons (Leu69Pro, His70Arg, His70Asn, Pro72Gln, Pro72Leu) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The variant is found in LQT panel(s). -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 11, 2019

Variant summary: KCNH2 c.211G>C (p.Gly71Arg) results in a non-conservative amino acid change located in the PAS domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225120 control chromosomes (gnomAD). c.211G>C causes the same amino acid change (i.e. p.Gly71Arg) as variant c.211G>A. p.Gly71Arg has been reported in the literature (either linked to c.211G>C or c.211G>A or not specified) in individuals affected with Long QT Syndrome (Itoh_2016, Lieve_2013, Mullally_2013, Raju_2013, Itoh_2010, Napolitano_2005). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in deficient protein trafficking to the cell membrane, which is suggested to be the dominant mechanism associated with type 2 Long QT syndrome. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

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:16414944). 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	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.64
MutPred		0.85		Gain of MoRF binding (P = 0.0324);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.93
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: rs199473420; hg19: chr7-150671895;