NM_000238.4(KCNH2):c.2617G>A (p.Gly873Ser) AND not provided

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Nov 17, 2020
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:: RCV000058144.16

Allele description [Variation Report for NM_000238.4(KCNH2):c.2617G>A (p.Gly873Ser)]

NM_000238.4(KCNH2):c.2617G>A (p.Gly873Ser)

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.2617G>A (p.Gly873Ser)

HGVS:

NC_000007.14:g.150948519C>T
NG_008916.1:g.34408G>A
NM_000238.4:c.2617G>AMANE SELECT
NM_172057.3:c.1597G>A
NP_000229.1:p.Gly873Ser
NP_000229.1:p.Gly873Ser
NP_742054.1:p.Gly533Ser
LRG_288t1:c.2617G>A
LRG_288:g.34408G>A
LRG_288p1:p.Gly873Ser
NC_000007.13:g.150645607C>T
NM_000238.2:c.2617G>A
NM_000238.3:c.2617G>A

Protein change:

G533S

Links:

dbSNP: rs41314354

NCBI 1000 Genomes Browser:

rs41314354

Molecular consequence:

NM_000238.4:c.2617G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1597G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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reticulocalbin-3 precursor [Homo sapiens]
reticulocalbin-3 precursor [Homo sapiens]
gi|28626510|ref|NP_065701.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000089664	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 16487223, 14661677, 16043162, 19841300, 22581653
SCV001550728	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing
SCV001771677	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Nov 17, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000089664

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

no classification provided

not provided

germline

literature only

PubMed (5)
[See all records that cite these PMIDs]

SCV001550728

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Likely benign

unknown

clinical testing

SCV001771677

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Nov 17, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genetic polymorphisms in KCNQ1, HERG, KCNE1 and KCNE2 genes in the Chinese, Malay and Indian populations of Singapore.

Koo SH, Ho WF, Lee EJ.

Br J Clin Pharmacol. 2006 Mar;61(3):301-8.

PubMed [citation]

PMID:: 16487223
PMCID:: PMC1885019

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.

Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME.

Mayo Clin Proc. 2003 Dec;78(12):1479-87.

PubMed [citation]

PMID:: 14661677

See all PubMed Citations (5)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089664.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

This variant has been reported in the following publications (PMID:16487223;PMID:14661677;PMID:16043162;PMID:19841300).

#	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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550728.1

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

Description

The KCNH2 p.Gly533Ser variant was identified in 1 of 156 proband chromosomes (frequency: 0.0064) from a 57 year old Han Chinese woman with Brugada syndrome; the variant was also found in in 2 of 1000 control chromosomes (frequency: 0.002) from healthy Han Chinese individuals (Verker_2005_PMID:16043162). In a study of 744 apparently healthy individuals, the p.G533S variant was identified in 0.3% of African individuals but was not identified in the Caucasian, Asian or Hispanic individuals (Ackerman_2003_PMID:14661677). Another study identified the variant at a frequency of 0.002 in 265 healthy Chinese individuals (Koo_2006_PMID:16487223). The variant was identified in dbSNP (ID: rs41314354), LOVD 3.0 and ClinVar (classified as likely benign by Invitae, Color and Biesecker Lab/Clinical Genomics Section, National Institutes of Health). The variant was identified in control databases in 74 of 281626 chromosomes at a frequency of 0.0002628 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 57 of 24918 chromosomes (freq: 0.002288), East Asian in 13 of 19928 chromosomes (freq: 0.000652), Latino in 2 of 35424 chromosomes (freq: 0.000056) and European (non-Finnish) in 2 of 128482 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a difference in splicing. The p.Gly533 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Functional data suggest that the p.G533S variant may be a modifer of K+ channel function (Verker_2005_PMID:16043162). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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

From GeneDx, SCV001771677.1

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

Description

Reported in association with Brugada syndrome and hypertrophic cardiomyopathy (Verkerk et al., 2005; Lopes et al., 2015); Also observed in multiple control individuals and individuals who underwent genetic testing for indications unrelated to cardiomyopathy, arrhythmia or a family history of sudden cardiac death (Ackerman et al., 2003; Verkerk et al., 2005; Koo et al., 2006; Kapa et al., 2009; Ng et al., 2013; Ghouse et al., 2016; Van Driest et al., 2016); Reported in ClinVar (ClinVar Variant ID# 67419; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32145446, 30821013, 16043162, 22949429, 26746457, 27711072, 19841300, 16487223, 14661677, 23861362, 25351510, 23414114)

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

Last Updated: Oct 20, 2024

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