NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 10, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002407094.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr)]

NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr)

Gene:

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr)

HGVS:

NC_000007.14:g.150951471G>T
NG_008916.1:g.31456C>A
NM_000238.4:c.1922C>AMANE SELECT
NM_001204798.2:c.902C>A
NM_001406753.1:c.1634C>A
NM_001406755.1:c.1745C>A
NM_001406756.1:c.1634C>A
NM_001406757.1:c.1622C>A
NM_172056.3:c.1922C>A
NM_172057.3:c.902C>A
NP_000229.1:p.Ser641Tyr
NP_000229.1:p.Ser641Tyr
NP_001191727.1:p.Ser301Tyr
NP_001393682.1:p.Ser545Tyr
NP_001393684.1:p.Ser582Tyr
NP_001393685.1:p.Ser545Tyr
NP_001393686.1:p.Ser541Tyr
NP_742053.1:p.Ser641Tyr
NP_742053.1:p.Ser641Tyr
NP_742054.1:p.Ser301Tyr
NP_742054.1:p.Ser301Tyr
LRG_288t1:c.1922C>A
LRG_288t2:c.1922C>A
LRG_288t3:c.902C>A
LRG_288:g.31456C>A
LRG_288p1:p.Ser641Tyr
LRG_288p2:p.Ser641Tyr
LRG_288p3:p.Ser301Tyr
NC_000007.13:g.150648559G>T
NM_000238.3:c.1922C>A
NM_172056.2:c.1922C>A
NM_172057.2:c.902C>A
NR_176254.1:n.2330C>A
NR_176255.1:n.1203C>A

Protein change:

S301Y

Links:

dbSNP: rs199472971

NCBI 1000 Genomes Browser:

rs199472971

Molecular consequence:

NM_000238.4:c.1922C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.902C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1634C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1745C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1634C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1622C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1922C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.902C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002720658	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 10, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15371638, 33450182 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002720658

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 10, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

S641 contributes HERG K+ channel inactivation.

Bian JS, Cui J, Melman Y, McDonald TV.

Cell Biochem Biophys. 2004;41(1):25-40.

PubMed [citation]

PMID:: 15371638

Cryo-EM Structure of K(+)-Bound hERG Channel Complexed with the Blocker Astemizole.

Asai T, Adachi N, Moriya T, Oki H, Maru T, Kawasaki M, Suzuki K, Chen S, Ishii R, Yonemori K, Igaki S, Yasuda S, Ogasawara S, Senda T, Murata T.

Structure. 2021 Mar 4;29(3):203-212.e4. doi: 10.1016/j.str.2020.12.007. Epub 2021 Jan 14.

PubMed [citation]

PMID:: 33450182

Details of each submission

From Ambry Genetics, SCV002720658.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.S641Y pathogenic mutation (also known as c.1922C>A), located in coding exon 7 of the KCNH2 gene, results from a C to A substitution at nucleotide position 1922. The serine at codon 641 is replaced by tyrosine, an amino acid with dissimilar properties. This variant has been detected in unrelated individuals with long QT syndrome, including a reported de novo occurrence (external communication). Based on internal analysis, this variant is predicted to be structurally disruptive (Bian JS et al. Cell Biochem Biophys, 2004;41:25-40; Asai T et al. Structure, 2021 Mar;29:203-212.e4; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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