NM_000238.4(KCNH2):c.1873G>C (p.Val625Leu) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 26, 2017
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:: RCV000756284.9

Allele description [Variation Report for NM_000238.4(KCNH2):c.1873G>C (p.Val625Leu)]

NM_000238.4(KCNH2):c.1873G>C (p.Val625Leu)

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.1873G>C (p.Val625Leu)

HGVS:

NC_000007.14:g.150951520C>G
NG_008916.1:g.31407G>C
NM_000238.4:c.1873G>CMANE SELECT
NM_001204798.2:c.853G>C
NM_001406753.1:c.1585G>C
NM_001406755.1:c.1696G>C
NM_001406756.1:c.1585G>C
NM_001406757.1:c.1573G>C
NM_172056.3:c.1873G>C
NM_172057.3:c.853G>C
NP_000229.1:p.Val625Leu
NP_000229.1:p.Val625Leu
NP_001191727.1:p.Val285Leu
NP_001393682.1:p.Val529Leu
NP_001393684.1:p.Val566Leu
NP_001393685.1:p.Val529Leu
NP_001393686.1:p.Val525Leu
NP_742053.1:p.Val625Leu
NP_742053.1:p.Val625Leu
NP_742054.1:p.Val285Leu
NP_742054.1:p.Val285Leu
LRG_288t1:c.1873G>C
LRG_288t2:c.1873G>C
LRG_288t3:c.853G>C
LRG_288:g.31407G>C
LRG_288p1:p.Val625Leu
LRG_288p2:p.Val625Leu
LRG_288p3:p.Val285Leu
NC_000007.13:g.150648608C>G
NM_000238.3:c.1873G>C
NM_172056.2:c.1873G>C
NM_172057.2:c.853G>C
NR_176254.1:n.2281G>C
NR_176255.1:n.1154G>C

Protein change:

V285L

Links:

dbSNP: rs1563156725

NCBI 1000 Genomes Browser:

rs1563156725

Molecular consequence:

NM_000238.4:c.1873G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.853G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1585G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1696G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1585G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1573G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1873G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.853G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000884049	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jun 26, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000884049

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Jun 26, 2017)

germline

clinical testing

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000884049.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.Val625Leu variant has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is also absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The valine at codon 625 is highly conserved considering 14 species up to Tetraodon (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on KCNH2 protein structure/function (SIFT: damaging, PolyPhen2probably damaging, and Mutation Taster: disease causing). Valine 625 is located in the pore region of KCNH2, and two other rare variants affecting this residue (p.Val625Ala and p.Val625Glu) have been reported in individuals included in long QT cohorts (Lieve 2013, Van Langen 2003, Giudicessi 2012). Additionally, several other rare variants in nearby amino acids have also been found in long QT patients (selected references: Kapplinger 2009, Splawski 2000, Kane 2014), and functional studies in cell culture have indicated that these variants (in addition to p.Val625Glu) impart trafficking defects to KCNH2 protein (Anderson 2014). Taken together, we interpret the p.Val625Leu variant to be likely pathogenic.

#	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: Mar 4, 2023

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