rs199473014

chr7-150947684-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_000238.4(KCNH2):c.2887C>A(p.Pro963Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000206 in 1,601,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P963?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 4.76

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 Uncertain_significance. Variant got 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150947683-GG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421672.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2887C>A	p.Pro963Thr	missense_variant	12/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2887C>A	p.Pro963Thr	missense_variant	12/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1867C>A	p.Pro623Thr	missense_variant	8/11	1
KCNH2	ENST00000684241.1	n.3720C>A		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000207 AC: 30 AN: 1448824 Hom.: 0 Cov.: 36 AF XY: 0.0000236 AC XY: 17 AN XY: 719732

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: 0.0000394

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces proline with threonine at codon 963 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has no detectable impact on membrane surface expression or biophysical gating properties (PMID: 29331839, 31493592). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19841300, 22949429, 28861002). This variant has also been reported in two related individuals affected with recurrent sudden infant death syndrome and in two other family members who had no cardiac phenotypes (PMID: 29331839). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 963 of the KCNH2 protein (p.Pro963Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome and/or sudden infant death syndrome (PMID: 19841300, 29331839). ClinVar contains an entry for this variant (Variation ID: 67449). 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 does not substantially affect KCNH2 function (PMID: 29331839, 31493592). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 07, 2017

The p.Pro963Thr variant (rs199473014) was reported in one patient in a cohort of ~400, and determined as one of C-terminal variants in KCNH2 with elevated allele frequency in Long-QT cases compared to controls (Kapa, 2009). Further analysis using a combination of prediction tools concluded this variant might be benign (Giudicessi, 2012). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.0009 percent (identified on 2 out of 214,534 chromosomes). It is also reported in ClinVar (Variation ID: 67449) without any clinical significance. The proline at position 963 is moderately conserved and computational analyses of the effects of the p.Pro963Thr variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro963Thr variant with certainty. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 25, 2023

This missense variant replaces proline with threonine at codon 963 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has no detectable impact on membrane surface expression or biophysical gating properties (PMID: 29331839, 31493592). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19841300, 22949429, 28861002). This variant has also been reported in two related individuals affected with recurrent sudden infant death syndrome and in two other family members who had no cardiac phenotypes (PMID: 29331839). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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: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	Benign	0.066
CardioboostArm	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.39	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0020	B;B
Vest4		0.55
MutPred		0.75		.;Gain of phosphorylation at P963 (P = 6e-04);
MVP		0.98
MPC		0.72
ClinPred		0.21	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.14
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199473014; hg19: chr7-150644772; COSMIC: COSV51225033; COSMIC: COSV51225033;