chr7-150952702-T-G

Position:

• chr7-150952702-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.1280A>C​(p.Tyr427Ser) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y427H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.86

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 11 ACMG points.

• PM1: In a topological_domain Extracellular (size 25) in uniprot entity KCNH2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 chr7-150952703-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-150952702-T-G is Pathogenic according to our data. Variant chr7-150952702-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67178.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=2}. Variant chr7-150952702-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1280A>C	p.Tyr427Ser	missense_variant	6/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1280A>C	p.Tyr427Ser	missense_variant	6/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2016	Variant summary: The KCNH2 c.1280A>C (p.Tyr427Ser) variant involves the alteration of a highly conserved nucleotide and is located in the ion transport domain at S1-S4 transmembrane region (InterPro, Itoh_2016). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 125938 control chromosomes, including the large and broad populations from ExAC. This variant has been reported as a pathogenic variant in literature found in at least two LQTS families; and in one family, the variant was found to be paternally inherited (Tester_2005, Kapa_2009, Giudicessi_2012, Itoh_2010, Itoh_2016). Other missense variants such as p.Tyr427His (PMIDs: 16414944, 16922724, and 22581653) and p.Tyr427Cys (PMIDs: 19716085 and 22581653) have also been reported in this codon, indicating that the codon is in a mutational hot-spot. One clinical diagnostic laboratory has classified this variant as likely pathogenic. Taken together, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2022	The p.Y427S variant (also known as c.1280A>C), located in coding exon 6 of the KCNH2 gene, results from an A to C substitution at nucleotide position 1280. The tyrosine at codon 427 is replaced by serine, an amino acid with dissimilar properties. This alteration is located in the S1/S2 transmembrane domain of HERG and has been detected in individuals with long QT syndrome (Kapa S et al. Circulation. 2009;120:1752-1760; Walsh R et al. Genet Med, 2021 01;23:47-58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2021

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67178). This missense change has been observed in individual(s) with possible long QT syndrome (PMID: 15840476, 22949429). This sequence change replaces tyrosine with serine at codon 427 of the KCNH2 protein (p.Tyr427Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. -

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	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.3	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.92
MutPred		0.86		.;Gain of helix (P = 0.0225);.;
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199472897; hg19: chr7-150649790;