NM_172056.2(KCNH2):c.2403G>T (p.Met801Ile) AND Long QT syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 7, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000703830.3

Allele description [Variation Report for NM_172056.2(KCNH2):c.2403G>T (p.Met801Ile)]

NM_172056.2(KCNH2):c.2403G>T (p.Met801Ile)

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_172056.2(KCNH2):c.2403G>T (p.Met801Ile)
HGVS:
  • NC_000007.14:g.150950163C>A
  • NG_008916.1:g.32764G>T
  • NM_000238.3:c.2398+5G>T
  • NM_001204798.2:c.1383G>T
  • NM_172056.2:c.2403G>T
  • NM_172057.2:c.1378+5G>T
  • NP_001191727.1:p.Met461Ile
  • NP_742053.1:p.Met801Ile
  • LRG_288t1:c.2398+5G>T
  • LRG_288t2:c.2403G>T
  • LRG_288t3:c.1378+5G>T
  • LRG_288:g.32764G>T
  • LRG_288p2:p.Met801Ile
  • NC_000007.13:g.150647251C>A
Protein change:
M461I
Links:
dbSNP: rs1554425149
NCBI 1000 Genomes Browser:
rs1554425149
Molecular consequence:
  • NM_000238.3:c.2398+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_172057.2:c.1378+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001204798.2:c.1383G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.2403G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976; OMIM: PS192500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000832751Invitaecriteria provided, single submitter
Pathogenic
(Aug 29, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001478567Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jan 7, 2021)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]
PMID:
15840476
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000832751.2

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

Description

This sequence change falls in intron 9 of the KCNH2 gene. It does not directly change the encoded amino acid sequence of the KCNH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 19841300). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478567.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: KCNH2 c.2398+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict that the variant weakens or abolishes a canonical 5-prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250960 control chromosomes. c.2398+5G>T has been reported in the literature in individuals affected with Long QT Syndrome (e.g. Tester_2005, Kapplinger_2009) and in individual with sudden unexpected death (Tester_2012) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 14, 2021

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