rs199472873

Variant names:

• chr7-150958224-G-A
• rs199472873
• NM_000238.4:c.751C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150958224-G-A
• chr7-150958224-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000238.4(KCNH2):​c.751C>T​(p.Pro251Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 1,223,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P251A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 2.31
• 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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.751C>T	p.Pro251Ser	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.751C>T	p.Pro251Ser	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000245 AC: 3 AN: 1223106 Hom.: 0 Cov.: 31 AF XY: 0.00000335 AC XY: 2 AN XY: 596746

African (AFR) AF: 0.00 AC: 0 AN: 24790

American (AMR) AF: 0.00 AC: 0 AN: 15840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18750

East Asian (EAS) AF: 0.00 AC: 0 AN: 26802

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3560

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 999588

Other (OTH) AF: 0.00 AC: 0 AN: 50098

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Jan 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 251 of the KCNH2 protein (p.Pro251Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Romano-Ward syndrome (PMID: 16414944). ClinVar contains an entry for this variant (Variation ID: 67523). -

Cardiovascular phenotype Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751C>T (p.P251S) alteration is located in exon 4 (coding exon 4) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 751, causing the proline (P) at amino acid position 251 to be replaced by a serine (S). Based on insufficient or conflicting evidence, 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:16414944). 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	0.071
CardioboostArm	Benign	0.0026
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.81	L;.
PhyloP100		2.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.64
Sift	Benign	0.30	T;.
Sift4G	Benign	0.22	T;T
Polyphen		0.90	P;.
Vest4		0.28
MutPred		0.73		Gain of phosphorylation at P251 (P = 0.007);.;
MVP		1.0
MPC		2.2
ClinPred		0.27	T
GERP RS		2.7
Varity_R		0.052
gMVP		0.56
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: rs199472873; hg19: chr7-150655312;