rs199472871

Variant names:

• chr7-150958253-G-A
• rs199472871
• NM_000238.4:c.722C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150958253-G-A
• chr7-150958253-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000238.4(KCNH2):​c.722C>T​(p.Pro241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,266,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P241S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.921
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29118386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.722C>T	p.Pro241Leu	missense_variant	Exon 4 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.722C>T	p.Pro241Leu	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000316 AC: 4 AN: 1266136 Hom.: 0 Cov.: 31 AF XY: 0.00000322 AC XY: 2 AN XY: 622080

African (AFR) AF: 0.00 AC: 0 AN: 25670

American (AMR) AF: 0.00 AC: 0 AN: 20426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20920

East Asian (EAS) AF: 0.00 AC: 0 AN: 27314

South Asian (SAS) AF: 0.00 AC: 0 AN: 63146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3836

European-Non Finnish (NFE) AF: 0.00000392 AC: 4 AN: 1021258

Other (OTH) AF: 0.00 AC: 0 AN: 51992

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH2: PM2, PS4:Moderate, PP3 -

Cardiovascular phenotype Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P241L variant (also known as c.722C>T), located in coding exon 4 of the KCNH2 gene, results from a C to T substitution at nucleotide position 722. The proline at codon 241 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in long QT syndrome cohorts (Shimizu W et al. J Am Coll Cardiol, 2009 Nov;54:2052-62; Walsh R et al. Genet Med, 2021 Jan;23:47-58). Limited functional studies have demonstrated membrane expression that is similar to wild-type levels (Perry MD et al. J Physiol, 2016 Jul;594:4031-49; Mattivi CL et al. Heart Rhythm, 2020 Feb;17:315-323). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19926013). 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	0.076
CardioboostArm	Benign	0.0027
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	7.5
DANN	Benign	0.83
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.61	T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.00080	T
MutationAssessor	Benign	0.69	N;.
PhyloP100		0.92
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.83	N;.
REVEL	Uncertain	0.60
Sift	Benign	0.35	T;.
Sift4G	Benign	0.41	T;T
Polyphen		0.0020	B;.
Vest4		0.20
MutPred		0.67		Loss of glycosylation at P241 (P = 0.0127);.;
MVP		0.99
MPC		1.0
ClinPred		0.074	T
GERP RS		-0.011
Varity_R		0.027
gMVP		0.51
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs199472871; hg19: chr7-150655341;