rs121912504

chr7-150951711-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):c.1682C>T(p.Ala561Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A561T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.76

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 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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 chr7-150951712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 7-150951711-G-A is Pathogenic according to our data. Variant chr7-150951711-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951711-G-A is described in Lovd as [Pathogenic]. Variant chr7-150951711-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1682C>T	p.Ala561Val	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1682C>T	p.Ala561Val	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as A561V leads to ion channel suppression (Kagan et al., 2000; Anderson et al., 2006; Li et al., 2007); Reported in ClinVar (ClinVar Variation ID#14420; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 19862833, 11009462, 11468227, 28718902, 17595376, 23303164, 16432067, 12354768, 7889573, 15840476, 19841300, 9927399, 27761161, 10973849, 11854117, 23139254, 24709866, 24606995, 15120823, 24667783, 22949429, 10753933, 18441445, 18593567, 26847485, 26823142, 19996378, 28316956, 28749187, 17445409, 24623279, 29672598, 30246897, 26582918, 31557540, 31737537, 32383558) -

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 14, 2000

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 561 of the KCNH2 protein (p.Ala561Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 7889573, 10973849, 18593567, 22949429, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14420). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 12354768, 16432067, 17445409, 23303164, 24623279). This variant disrupts the p.Ala561 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 23303164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

The p.A561V pathogenic mutation (also known as c.1682C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1682. The alanine at codon 561 is replaced by valine, an amino acid with similar properties, and is located in the S5, transmembrane spanning region. This alteration has been previously detected in multiple unrelated individuals reported to have long QT syndrome (LQTS), and was reported to segregate with disease in at least one family (Curran ME et al. Cell. 1995;80:795-803; Splawski I et al. Circulation. 2000;102:1178-85; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5:519-28; Christiansen M et al. BMC Med Genet. 2014;15:31). In addition, results from in vitro and in vivo studies indicate this alteration to result in deficient protein trafficking and altered ion channel function (Anderson CL et al. Circulation. 2006;113:365-73; Jou CJ et al. Circ Res. 2013;112:826-30; Mehta A et al. Cardiovasc Res. 2014;102:497-506; Li G et al. Mol Med Rep. 2016;13:2467-75). Furthermore, other alterations affecting this amino acid (p.A561T, c.1681G>A and p.A561P, c.1681G>C) have also been reported in association with LQTS (Dausse E et al. J Mol Cell Cardiol. 1996;28(8):1609-15; Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Obesity;C0151878:Prolonged QT interval Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 04, 2023

Variant summary: KCNH2 c.1682C>T (p.Ala561Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1682C>T has been reported in the literature in individuals affected with long QT syndrome and was reported to segregate with disease (examples: Curran_1995, Giudicessi_2012, Riuro_2015). These data indicate that the variant is very likely to be associated with disease. Multiple studies have shown that this variant impairs normal protein function (examples : Anderson_2006, Li_2007, Jou_2013). Other variants affecting this residue (p.Ala561Pro, p.Ala561Thr) have been classified pathogenic in ClinVar. The following publications have been ascertained in the context of this evaluation (PMID: 7889573, 16432067, 17445409, 22949429, 22949429, 24667783). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. 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:7889573;PMID:9927399;PMID:10973849;PMID:11113008;PMID:11468227;PMID:11668638;PMID:11854117;PMID:15051636;PMID:15840476;PMID:16432067;PMID:17160940;PMID:17445409;PMID:18441445;PMID:18593567;PMID:19716085;PMID:19841300;PMID:9024139). 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
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.93
MutPred		0.91		.;Loss of catalytic residue at T556 (P = 0.5076);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.97

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: rs121912504; hg19: chr7-150648799; COSMIC: COSV51212273;