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NM_000238.4(KCNH2):c.647C>T (p.Thr216Ile) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 29, 2020
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:
RCV000706092.9

Allele description [Variation Report for NM_000238.4(KCNH2):c.647C>T (p.Thr216Ile)]

NM_000238.4(KCNH2):c.647C>T (p.Thr216Ile)

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.647C>T (p.Thr216Ile)
HGVS:
  • NC_000007.14:g.150958328G>A
  • NG_008916.1:g.24599C>T
  • NM_000238.4:c.647C>TMANE SELECT
  • NM_001406753.1:c.359C>T
  • NM_001406755.1:c.470C>T
  • NM_001406756.1:c.359C>T
  • NM_001406757.1:c.347C>T
  • NM_172056.3:c.647C>T
  • NP_000229.1:p.Thr216Ile
  • NP_000229.1:p.Thr216Ile
  • NP_001393682.1:p.Thr120Ile
  • NP_001393684.1:p.Thr157Ile
  • NP_001393685.1:p.Thr120Ile
  • NP_001393686.1:p.Thr116Ile
  • NP_742053.1:p.Thr216Ile
  • NP_742053.1:p.Thr216Ile
  • LRG_288t1:c.647C>T
  • LRG_288t2:c.647C>T
  • LRG_288:g.24599C>T
  • LRG_288p1:p.Thr216Ile
  • LRG_288p2:p.Thr216Ile
  • NC_000007.13:g.150655416G>A
  • NM_000238.3:c.647C>T
  • NM_172056.2:c.647C>T
  • NR_176254.1:n.1055C>T
Protein change:
T116I
Links:
dbSNP: rs1563170569
NCBI 1000 Genomes Browser:
rs1563170569
Molecular consequence:
  • NM_000238.4:c.647C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.470C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.347C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.647C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000835124Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 29, 2020) 		germlineclinical testing

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

Help

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000835124.5

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

Description

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNH2-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces threonine with isoleucine at codon 216 of the KCNH2 protein (p.Thr216Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024