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NM_000238.4(KCNH2):c.1969G>A (p.Gly657Ser) AND Congenital long QT syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jun 7, 2021
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:
RCV000058068.8

Allele description [Variation Report for NM_000238.4(KCNH2):c.1969G>A (p.Gly657Ser)]

NM_000238.4(KCNH2):c.1969G>A (p.Gly657Ser)

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.1969G>A (p.Gly657Ser)
Other names:
NM_000238.3:c.1969G>A;p.Gly657Ser
HGVS:
  • NC_000007.14:g.150951097C>T
  • NG_008916.1:g.31830G>A
  • NM_000238.2:c.1969G>A
  • NM_000238.4:c.1969G>AMANE SELECT
  • NM_001204798.2:c.949G>A
  • NM_001406753.1:c.1681G>A
  • NM_001406755.1:c.1792G>A
  • NM_001406756.1:c.1681G>A
  • NM_001406757.1:c.1669G>A
  • NM_172056.3:c.1969G>A
  • NM_172057.3:c.949G>A
  • NP_000229.1:p.Gly657Ser
  • NP_000229.1:p.Gly657Ser
  • NP_001191727.1:p.Gly317Ser
  • NP_001393682.1:p.Gly561Ser
  • NP_001393684.1:p.Gly598Ser
  • NP_001393685.1:p.Gly561Ser
  • NP_001393686.1:p.Gly557Ser
  • NP_742053.1:p.Gly657Ser
  • NP_742053.1:p.Gly657Ser
  • NP_742054.1:p.Gly317Ser
  • NP_742054.1:p.Gly317Ser
  • LRG_288t1:c.1969G>A
  • LRG_288t2:c.1969G>A
  • LRG_288t3:c.949G>A
  • LRG_288:g.31830G>A
  • LRG_288p1:p.Gly657Ser
  • LRG_288p2:p.Gly657Ser
  • LRG_288p3:p.Gly317Ser
  • NC_000007.13:g.150648185C>T
  • NM_000238.3:c.1969G>A
  • NM_172056.2:c.1969G>A
  • NM_172057.2:c.949G>A
  • NR_176254.1:n.2377G>A
  • NR_176255.1:n.1250G>A
Protein change:
G317S
Links:
dbSNP: rs199472978
NCBI 1000 Genomes Browser:
rs199472978
Molecular consequence:
  • NM_000238.4:c.1969G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1681G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1792G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1681G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1669G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1969G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Congenital long QT syndrome (RWS)
Synonyms:
Familial long QT syndrome; Romano-Ward syndrome; Ventricular fibrillation with prolonged QT interval
Identifiers:
MONDO: MONDO:0019171; MedGen: C1141890; Orphanet: 768; OMIM: PS192500

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000089588Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
no classification provided
not providedgermlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001736711Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Jun 7, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical testing, literature only

Citations

PubMed

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]
PMID:
22581653
PMCID:
PMC4640174

QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome.

Seethala S, Singh P, Shusterman V, Ribe M, Haugaa KH, Němec J.

J Am Heart Assoc. 2015 Dec 16;4(12). doi:pii: e002395. 10.1161/JAHA.115.002395.

PubMed [citation]
PMID:
26675252
PMCID:
PMC4845278
See all PubMed Citations (7)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089588.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001736711.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.Gly657Ser variant in KCNH2 has been previously reported in 1 individual referred for long QT syndrome (LQTS) genetic testing, and it has also been observed in 3 individuals with a reported diagnosis of LQTS by a clinical testing laboratory (Kapplinger 2009, personal communication ClinVar SCV000261846.3). It was absent from large population studies. In vitro functional studies have demonstrated an impact to normal KCNH2 potassium channel function, including when the variant is co-expressed with wild-type (Perry 2016, Hardman 2007). This variant is located in the transmembrane spanning S5/pore region of the KCNH2 protein, which has been deemed important for proper channel function (Kapa 2009 PMID: 19841300).Computational prediction tools and conservation analyses suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PM2_Supporting, PP3, PM1, PS3_Supporting, PS4_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Oct 8, 2024