NM_000238.4(KCNH2):c.1882G>A (p.Gly628Ser) AND not provided

Clinical significance:Pathogenic (Last evaluated: Feb 25, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000223848.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.1882G>A (p.Gly628Ser)]

NM_000238.4(KCNH2):c.1882G>A (p.Gly628Ser)

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.1882G>A (p.Gly628Ser)
HGVS:
  • NC_000007.14:g.150951511C>T
  • NG_008916.1:g.31416G>A
  • NM_000238.3:c.1882G>A
  • NM_000238.4:c.1882G>AMANE SELECT
  • NM_001204798.2:c.862G>A
  • NM_172056.2:c.1882G>A
  • NM_172057.3:c.862G>A
  • NP_000229.1:p.Gly628Ser
  • NP_000229.1:p.Gly628Ser
  • NP_001191727.1:p.Gly288Ser
  • NP_742053.1:p.Gly628Ser
  • NP_742054.1:p.Gly288Ser
  • LRG_288t1:c.1882G>A
  • LRG_288t2:c.1882G>A
  • LRG_288:g.31416G>A
  • LRG_288p1:p.Gly628Ser
  • LRG_288p2:p.Gly628Ser
  • NC_000007.13:g.150648599C>T
  • NM_000238.2:c.1882G>A
  • Q12809:p.Gly628Ser
Protein change:
G288S; GLY628SER
Links:
UniProtKB: Q12809#VAR_008583; OMIM: 152427.0008; dbSNP: rs121912507
NCBI 1000 Genomes Browser:
rs121912507
Molecular consequence:
  • NM_000238.3:c.1882G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000238.4:c.1882G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.862G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.1882G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.862G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
6

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000280122Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Nov 15, 2013)
germlineclinical testing

SCV000490550GeneDxcriteria provided, single submitter
Pathogenic
(Feb 25, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided6not providednot providednot providednot providedclinical testing

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280122.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Gly628Ser Based on the data reviewed below we consider this variant likely disease-causing. The variant has been seen in at least 6 unrelated cases of Long QT. There is no segregation data available. Curran et al (1995) was the first to report this variant in a proband with Long QT suggesting the connection between LongQt and KCNH2 (then known as the HERG gene). It was a de novo mutation. No clinical data or segregation data was given. Splawski et al. (2000) reported this variant in two families with LQT from a cohort of 262 individuals with LQTS. The authors tested for mutations in all known arrhythmia genes. No specific phenotype data was given for the patients. Lupoglazoff et al (2004) reported this variant in a neonate with fetal bradycardia and heart failure. This was a de novo mutation. No segregation data was given. Shim et al. 2005 reported this variant in a neonate with congenital LQT and a double heterozygote for a novel SCN5A varaint-V1950L. The patient was implanted with an ICD at 3 days. The patient's mother had LQT and the SCN5A mutation. The father did not carry the KCNH2 variant and it was thus de novo and thought to contribute to the patient's phenotype. Kapa et al., 2009 (Ackerman) reported this variant in one individual from their cohort of 388 LQT syndrome patients from 1997 to 2007. All had a clinical diagnostic score (Schwartz score) of >4 or a corrected QT interval (QTc) >480 ms. They did mutation analysis for KCNQ1, KCNH2, and SCN5A. Specific case data was not given for the patient with this variant. They reported an extremely high probability (EPV100%; 95% CI, 95 to 100) of pathogenicity for missense mutations localizing to the linker, transmembrane, and pore regions of KCNH2 but lower EPVs for missense mutations in the N terminus (63%; 95% CI, 17 to 84) or C terminus of KCNH2. This variant occurs in the pore-forming domain, which is highly conserved in all potassium channel subunits (Curran et al. 1995). This substitution in vitro caused potassium ion selectivity loss. This substitution has also been found to correctly insert into the cell surface membrane, but does not generate Kv11.1 channel function, presumable because of its location within the potassium selectivity filter (Anderson et al. 2006). This variant results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine, at a position that is highly conserved. Other variants have been reported in association with disease at this codon (Gly628Ala, Gly628Val) and nearby codons (Phe627Leu, Phe627Ile, Asn629Asp, Asn629Ser, Asn629Thr, Asn629Ile, Asn629Lys). In total the variant has not been seen in ~8,100 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 628 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/22/13). The variant was not observed in the following published control samples: Kapa did not report this variant in >1300 control individuals, Lupoglazoff did not report this variant in 100 control individuals, Splawski did not report this variant in 200 control individuals.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided6not providednot providednot provided

From GeneDx, SCV000490550.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The G628S pathogenic variant in the KCNH2 gene has been reported multiple times in association with LQTS, and was not seen in >1,369 healthy control individuals (Curran et al., 1995; Splawski et al., 2000; Shim et al., 2005; Anderson et al., 2006; Kapa et al., 2009; Giudicessi et al., 2012). Of note, G628S was identified as a de novo variant in a neonate presenting with fetal bradycardia, torsades de pointes, 2:1 atrioventricular block, a QTc of 544 ms, and heart failure; family history was negative and both parents had a normal QTc interval (Lupoglazoff et al., 2004). Furthermore, the G628S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G628S variant results in a non-conservative amino acid substitution of a non-polar Glycine residue with a polar Serine residue, at a position that is highly conserved and important for potassium ion selectivity (Curran et al., 1995). The G628S variant is located in the pore-forming domain of the protein and alters the selectivity filter motif (Curran et al., 1995). Multiple functional studies demonstrated that G628S results in a loss of potassium channel function (Anderson et al., 2006; Brunner et al., 2008; Ren et al., 2010). In summary, G628S in the KCNH2 gene is interpreted as a pathogenic variant.

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

Last Updated: Nov 27, 2021

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