NM_000238.3(KCNH2):c.2510A>G (p.Asp837Gly) AND not provided

Clinical significance:Pathogenic (Last evaluated: Mar 5, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000181873.3

Allele description [Variation Report for NM_000238.3(KCNH2):c.2510A>G (p.Asp837Gly)]

NM_000238.3(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_000238.3(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_000238.3:c.2510A>G
  • NM_172057.2:c.1490A>G
  • NP_000229.1:p.Asp837Gly
  • NP_742054.1:p.Asp497Gly
  • LRG_288t1:c.2510A>G
  • LRG_288t3:c.1490A>G
  • LRG_288:g.33989A>G
  • LRG_288p1:p.Asp837Gly
  • LRG_288p3:p.Asp497Gly
  • NC_000007.13:g.150646026T>C
  • NM_000238.2:c.2510A>G
  • Q12809:p.Asp837Gly
Protein change:
D497G
Links:
UniProtKB: Q12809#VAR_068280; dbSNP: rs199473004
NCBI 1000 Genomes Browser:
rs199473004
Molecular consequence:
  • NM_000238.3:c.2510A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.2:c.1490A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000234176GeneDxcriteria provided, single submitter
Pathogenic
(Mar 5, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000234176.8

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

Description

The D837G pathogenic variant in the KCNH2 gene has been reported previously in association with LQTS, and this variant was absent from 1,488 control alleles (Khositseth et al., 2004; Tester et al., 2005; Partemi et al., 2014). In addition, the NHLBI Exome Sequencing Project reports D837G was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The D837G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species and islocated in the cyclic-nucleotide-binding homology domain (CNBHD). Moreover, functional studies have shown that variants in the CNBHD can cause incorrect folding that can lead to protein instability and ultimately deficient protein trafficking (Li et al., 2016; Anderson et al., 2014). Furthermore, pathogenic missense variants at the same residue (D837N, D837Y), as well as variants in nearby residues (R835W, R835Q, V841L, P846S, P846T) have been reported in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, D837G 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: Oct 8, 2021

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