VCV002136625.4 - ClinVar

NM_000238.4(KCNH2):c.2134G>A (p.Asp712Asn)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000238.4(KCNH2):c.2134G>A (p.Asp712Asn)

Variation ID: 2136625 Accession: VCV002136625.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q36.1 7: 150950932 (GRCh38) [ NCBI UCSC ] 7: 150648020 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	May 1, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000238.4:c.2134G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000229.1:p.Asp712Asn	missense
NM_001204798.2:c.1114G>A	NP_001191727.1:p.Asp372Asn	missense
NM_001406753.1:c.1846G>A	NP_001393682.1:p.Asp616Asn	missense
NM_001406755.1:c.1957G>A	NP_001393684.1:p.Asp653Asn	missense
NM_001406756.1:c.1846G>A	NP_001393685.1:p.Asp616Asn	missense
NM_001406757.1:c.1834G>A	NP_001393686.1:p.Asp612Asn	missense
NM_172056.3:c.2134G>A	NP_742053.1:p.Asp712Asn	missense
NM_172057.3:c.1114G>A	NP_742054.1:p.Asp372Asn	missense
NR_176254.1:n.2542G>A
NR_176255.1:n.1415G>A
NC_000007.14:g.150950932C>T
NC_000007.13:g.150648020C>T
NG_008916.1:g.31995G>A
LRG_288:g.31995G>A
LRG_288t1:c.2134G>A	LRG_288p1:p.Asp712Asn
LRG_288t2:c.2134G>A	LRG_288p2:p.Asp712Asn
LRG_288t3:c.1114G>A	LRG_288p3:p.Asp372Asn

... more HGVS ... less HGVS

Protein change

D372N, D616N, D653N, D712N, D612N

Other names

Canonical SPDI

NC_000007.14:150950931:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KCNH2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3223	3309

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 8, 2024	RCV003062148.3
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Dec 9, 2022	RCV003170966.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440734.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 26669661 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 712 of the KCNH2 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 712 of the KCNH2 protein (p.Asp712Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 26669661). ClinVar contains an entry for this variant (Variation ID: 2136625). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. (less)
Uncertain significance (Dec 09, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003864697.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 26669661‚ 29766885 Comment: The p.D712N variant (also known as c.2134G>A), located in coding exon 8 of the KCNH2 gene, results from a G to A substitution at nucleotide … (more) The p.D712N variant (also known as c.2134G>A), located in coding exon 8 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2134. The aspartic acid at codon 712 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited (Hayashi K et al. JACC Clin Electrophysiol, 2016 Jun;2:279-287; Itoh H et al. Eur J Hum Genet, 2016 Aug;24:1160-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 712 of the KCNH2 protein (p.Asp712Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 26669661). ClinVar contains an entry for this variant (Variation ID: 2136625). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

Comment:

The p.D712N variant (also known as c.2134G>A), located in coding exon 8 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2134. The aspartic acid at codon 712 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited (Hayashi K et al. JACC Clin Electrophysiol, 2016 Jun;2:279-287; Itoh H et al. Eur J Hum Genet, 2016 Aug;24:1160-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Impact of Updated Diagnostic Criteria for Long QT Syndrome on Clinical Detection of Diseased Patients: Results From a Study of Patients Carrying Gene Mutations.	Hayashi K	JACC. Clinical electrophysiology	2016	PMID: 29766885
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.	Itoh H	European journal of human genetics : EJHG	2016	PMID: 26669661

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000238.4(KCNH2):c.2134G>A (p.Asp712Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...