rs199472884

chr7-150958059-C-Achr7-150958059-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):c.916G>T(p.Gly306Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000632 in 1,108,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 0.251

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150958059-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67543.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-150958059-C-A is Pathogenic according to our data. Variant chr7-150958059-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150958059-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.916G>T	p.Gly306Trp	missense_variant, splice_region_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.916G>T	p.Gly306Trp	missense_variant, splice_region_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1139G>T		splice_region_variant, non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1749G>T		splice_region_variant, non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000632 AC: 7 AN: 1108190 Hom.: 0 Cov.: 31 AF XY: 0.00000762 AC XY: 4 AN XY: 525060

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: 0.00

Gnomad4 NFE exome AF: 0.00000746

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2016

The G306W variant in the KCNH2 gene has been reported in at least one individual with LQTS and has not been observed in >1000 control alleles (Tester D et al., 2005; Kapa et al., 2009; Giudicessi et al., 2012). Of note, coverage of this nucleotide position in these control alleles was not reported, and presence or absence in the NHLBI Exome Sequencing Project was unable to be determined due to inadequate coverage (1X). This variant was also seen co-segregating with LQTS in four relatives referred for genetic testing at GeneDx. Additionally, G306W is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Guanine nucleotide at position c.916 is the 3'-terminal nucleotide of exon 4, and two out of three splicing algorithms suggest that this nucleotide substitution either damages or destroys the canonical splice donor site at this exon/intron junction. Other missense variants in KCNH2 that are predicted to affect splicing have been reported in the Human Genome Database (HGMD) in association with LQTS (Stenson et al., 2014). Lastly, a variant at the same residue (G306R) has also been reported in HGMD in association with LQTS. Therefore, G306W is a strong candidate to be pathogenic. Nevertheless, additional segregation and functional studies are necessary to clarify the role of this variant in disease. -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 306 of the KCNH2 protein (p.Gly306Trp). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 22949429; Invitae). ClinVar contains an entry for this variant (Variation ID: 67544). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.916G nucleotide in the KCNH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15840476, 18752142; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: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	Pathogenic	0.77
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.64
MutPred		0.79		Loss of disorder (P = 0.0176);.;
MVP		0.99
MPC		1.5
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.67
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199472884; hg19: chr7-150655147;