rs199472886

Positions:

• chr7-150957460-G-A
• chr7-150957460-G-C
• chr7-150957460-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BS2_Supporting

The NM_000238.4(KCNH2):​c.959C>T​(p.Ser320Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S320W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 9.83

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 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity KCNH2_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• BS2: High AC in GnomAdExome4 at 7 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.959C>T	p.Ser320Leu	missense_variant	5/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.959C>T	p.Ser320Leu	missense_variant	5/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1182C>T		non_coding_transcript_exon_variant	5/9	2
KCNH2	ENST00000684241.1	n.1792C>T		non_coding_transcript_exon_variant	3/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250452 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727178

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000106 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

This sequence change in KCNH2 is predicted to replace serine with leucine at codon 320, p.(Ser320Leu). The serine residue is highly conserved (100 vertebrates, UCSC), and is located in the N-terminus region, amino acids 306-403, which is defined as a mutational hot spot (PMID: 32893267). There is a large physicochemical difference between serine and leucine. The variant is present in a single European (non-Finnish) individual in the population database gnomAD v2.1 (1/113,016 alleles). This variant has been reported in at least three probands with long QT syndrome (PMID: 15840476, 18441445, 19695459). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.846). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1_Supporting, PM2_Supporting, PP3, PS4_Supporting. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 31, 2021

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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of long QT syndrome (PMID: 15840476, 19695459). ClinVar contains an entry for this variant (Variation ID: 67550). This variant is present in population databases (rs199472886, ExAC 0.002%). This sequence change replaces serine with leucine at codon 320 of the KCNH2 protein (p.Ser320Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2021

The c.959C>T (p.S320L) alteration is located in exon 5 (coding exon 5) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 959, causing the serine (S) at amino acid position 320 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 19, 2021

- -

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). 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	0.94
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.86	P;.
Vest4		0.76
MutPred		0.78		Loss of disorder (P = 0.0292);.;
MVP		0.99
MPC		1.1
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.37
gMVP		0.73

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: rs199472886; hg19: chr7-150654548;