NM_000238.4(KCNH2):c.1894C>G (p.Pro632Ala) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 15, 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:: RCV001362441.6

Allele description [Variation Report for NM_000238.4(KCNH2):c.1894C>G (p.Pro632Ala)]

NM_000238.4(KCNH2):c.1894C>G (p.Pro632Ala)

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.1894C>G (p.Pro632Ala)

HGVS:

NC_000007.14:g.150951499G>C
NG_008916.1:g.31428C>G
NM_000238.4:c.1894C>GMANE SELECT
NM_001204798.2:c.874C>G
NM_001406753.1:c.1606C>G
NM_001406755.1:c.1717C>G
NM_001406756.1:c.1606C>G
NM_001406757.1:c.1594C>G
NM_172056.3:c.1894C>G
NM_172057.3:c.874C>G
NP_000229.1:p.Pro632Ala
NP_000229.1:p.Pro632Ala
NP_001191727.1:p.Pro292Ala
NP_001393682.1:p.Pro536Ala
NP_001393684.1:p.Pro573Ala
NP_001393685.1:p.Pro536Ala
NP_001393686.1:p.Pro532Ala
NP_742053.1:p.Pro632Ala
NP_742053.1:p.Pro632Ala
NP_742054.1:p.Pro292Ala
NP_742054.1:p.Pro292Ala
LRG_288t1:c.1894C>G
LRG_288t2:c.1894C>G
LRG_288t3:c.874C>G
LRG_288:g.31428C>G
LRG_288p1:p.Pro632Ala
LRG_288p2:p.Pro632Ala
LRG_288p3:p.Pro292Ala
NC_000007.13:g.150648587G>C
NM_000238.3:c.1894C>G
NM_172056.2:c.1894C>G
NM_172057.2:c.874C>G
NR_176254.1:n.2302C>G
NR_176255.1:n.1175C>G

Protein change:

P292A

Links:

dbSNP: rs199473527

NCBI 1000 Genomes Browser:

rs199473527

Molecular consequence:

NM_000238.4:c.1894C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.874C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1606C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1717C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1606C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1594C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1894C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.874C>G - 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
SCV001558457	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 15, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23174487, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001558457

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 15, 2021)

germline

clinical testing

PubMed (2)
[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

Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

Mullally J, Goldenberg I, Moss AJ, Lopes CM, Ackerman MJ, Zareba W, McNitt S, Robinson JL, Benhorin J, Kaufman ES, Towbin JA, Barsheshet A.

Heart Rhythm. 2013 Mar;10(3):378-82. doi: 10.1016/j.hrthm.2012.11.006. Epub 2012 Nov 19.

PubMed [citation]

PMID:: 23174487
PMCID:: PMC3690288

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, SCV001558457.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 23174487). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 632 of the KCNH2 protein (p.Pro632Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine.

#	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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