NM_000238.4(KCNH2):c.1280A>C (p.Tyr427Ser) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 3, 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:: RCV001854188.5

Allele description [Variation Report for NM_000238.4(KCNH2):c.1280A>C (p.Tyr427Ser)]

NM_000238.4(KCNH2):c.1280A>C (p.Tyr427Ser)

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.1280A>C (p.Tyr427Ser)

HGVS:

NC_000007.14:g.150952702T>G
NG_008916.1:g.30225A>C
NM_000238.4:c.1280A>CMANE SELECT
NM_001204798.2:c.260A>C
NM_001406753.1:c.992A>C
NM_001406755.1:c.1103A>C
NM_001406756.1:c.992A>C
NM_001406757.1:c.980A>C
NM_172056.3:c.1280A>C
NM_172057.3:c.260A>C
NP_000229.1:p.Tyr427Ser
NP_000229.1:p.Tyr427Ser
NP_001191727.1:p.Tyr87Ser
NP_001393682.1:p.Tyr331Ser
NP_001393684.1:p.Tyr368Ser
NP_001393685.1:p.Tyr331Ser
NP_001393686.1:p.Tyr327Ser
NP_742053.1:p.Tyr427Ser
NP_742053.1:p.Tyr427Ser
NP_742054.1:p.Tyr87Ser
NP_742054.1:p.Tyr87Ser
LRG_288t1:c.1280A>C
LRG_288t2:c.1280A>C
LRG_288t3:c.260A>C
LRG_288:g.30225A>C
LRG_288p1:p.Tyr427Ser
LRG_288p2:p.Tyr427Ser
LRG_288p3:p.Tyr87Ser
NC_000007.13:g.150649790T>G
NM_000238.3:c.1280A>C
NM_172056.2:c.1280A>C
NM_172057.2:c.260A>C
NR_176254.1:n.1688A>C
NR_176255.1:n.561A>C
Q12809:p.Tyr427Ser

Protein change:

Y327S

Links:

UniProtKB: Q12809#VAR_068261; dbSNP: rs199472897

NCBI 1000 Genomes Browser:

rs199472897

Molecular consequence:

NM_000238.4:c.1280A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.260A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.992A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1103A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.992A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.980A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1280A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.260A>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002133689	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 3, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15840476, 22949429, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002133689

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 3, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]

PMID:: 22949429
PMCID:: PMC3705705

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002133689.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (ExAC no frequency). 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 67178). This missense change has been observed in individual(s) with possible long QT syndrome (PMID: 15840476, 22949429). This sequence change replaces tyrosine with serine at codon 427 of the KCNH2 protein (p.Tyr427Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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