NM_000238.4(KCNH2):c.2510A>G (p.Asp837Gly) AND Long QT syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 30, 2024
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:: RCV000469039.17

Allele description [Variation Report for NM_000238.4(KCNH2):c.2510A>G (p.Asp837Gly)]

NM_000238.4(KCNH2):c.2510A>G (p.Asp837Gly)

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.2510A>G (p.Asp837Gly)

Other names:

p.D837G:GAC>GGC; NM_000238.3(KCNH2):c.2510A>G(p.Asp837Gly); NM_172057.2(KCNH2):c.1490A>G(p.Asp497Gly)

HGVS:

NC_000007.14:g.150948938T>C
NG_008916.1:g.33989A>G
NM_000238.4:c.2510A>GMANE SELECT
NM_172057.3:c.1490A>G
NP_000229.1:p.Asp837Gly
NP_000229.1:p.Asp837Gly
NP_742054.1:p.Asp497Gly
LRG_288t1:c.2510A>G
LRG_288:g.33989A>G
LRG_288p1:p.Asp837Gly
NC_000007.13:g.150646026T>C
NM_000238.2:c.2510A>G
NM_000238.3:c.2510A>G
Q12809:p.Asp837Gly

Protein change:

D497G

Links:

UniProtKB: Q12809#VAR_068280; dbSNP: rs199473004

NCBI 1000 Genomes Browser:

rs199473004

Molecular consequence:

NM_000238.4:c.2510A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1490A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543440	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21440677, 25119684, 25417810, 19841300, 26669661, 28492532
SCV004827270	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15851119, 20850565, 21440677, 23631430, 25119684, 25417810, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543440

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004827270

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.

Itoh H, Berthet M, Fressart V, Denjoy I, Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Stallmeyer B, Zumhagen S, Shimizu W, Wilde AA, Schulze-Bahr E, Horie M, Tezenas du Montcel S, Guicheney P.

Eur J Hum Genet. 2016 Aug;24(8):1160-6. doi: 10.1038/ejhg.2015.257. Epub 2015 Dec 16.

PubMed [citation]

PMID:: 26669661
PMCID:: PMC4970673

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543440.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 837 of the KCNH2 protein (p.Asp837Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 21440677, 25119684; Invitae). ClinVar contains an entry for this variant (Variation ID: 67407). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). This variant disrupts the p.Asp837 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19841300, 26669661). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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

From All of Us Research Program, National Institutes of Health, SCV004827270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

The c.2510A>G (p.Asp837Gly) variant in the KCNH2 gene is predicted to replace aspartic acid with glycine at codon 837 (p.Asp837Gly). This variant has been reported in multiple individuals with long QT syndrome (PMID: 21440677, 15851119, 25119684, 20850565, 23631430). Experimental analysis of the variant in cultured cell line proved the deficient protein trafficking and the negative functional impact (PMID: 25417810). Alternative variants disrupting the same amino acid (p.Asp837Asn, p.Asp837Tyr) have been interpreted as pathogenic/likely pathogenic (ClinVar ID: 67405, 67406). The variant is reported in ClinVar (ID: 67407). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.959). Therefore, the c.2510A>G (p.Asp837Gly) variant of KCNH2 has been classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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