NM_000238.4(KCNH2):c.51C>G (p.Thr17=) AND not specified

Germline classification:: Benign/Likely benign (4 submissions)
Last evaluated:: May 30, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000181750.16

Allele description [Variation Report for NM_000238.4(KCNH2):c.51C>G (p.Thr17=)]

NM_000238.4(KCNH2):c.51C>G (p.Thr17=)

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.51C>G (p.Thr17=)

Other names:

p.T17T:ACC>ACG

HGVS:

NC_000007.14:g.150977863G>C
NG_008916.1:g.5064C>G
NM_000238.4:c.51C>GMANE SELECT
NM_172056.3:c.51C>G
NP_000229.1:p.Thr17=
NP_000229.1:p.Thr17=
NP_742053.1:p.Thr17=
NP_742053.1:p.Thr17=
LRG_288t1:c.51C>G
LRG_288t2:c.51C>G
LRG_288:g.5064C>G
LRG_288p1:p.Thr17=
LRG_288p2:p.Thr17=
NC_000007.13:g.150674951G>C
NM_000238.2:c.51C>G
NM_000238.3:c.51C>G
NM_172056.2:c.51C>G
NR_176254.1:n.459C>G

Links:

dbSNP: rs144338227

NCBI 1000 Genomes Browser:

rs144338227

Molecular consequence:

NR_176254.1:n.459C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000238.4:c.51C>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_172056.3:c.51C>G - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000234053	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Jan 17, 2013)	germline	clinical testing	Citation Link,
SCV001364011	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Oct 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001433188	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 30, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001923558	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.

Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G, Oyen N, Greve G, Carlsson A, Rognum TO, Hallerud M, Kongsgård E, Amlie JP, Leren TP.

Scand J Clin Lab Invest. 2008;68(5):362-8. doi: 10.1080/00365510701765643.

PubMed [citation]

PMID:: 18752142

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000234053.8

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001364011.1

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

Description

Variant summary: KCNH2 c.51C>G results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00061 in 240046 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.51C>G has been reported in the literature in individuals affected with Arrhythmia (Berge_2008). This report does not provide an unequivocal conclusion about association of the variant with Arrhythmia (Berge_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant twice as uncertain significance, twice as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign.

#	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 Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV001433188.1

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

#	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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001923558.1

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

#	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: Apr 13, 2025

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