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

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 20, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000246613.4

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:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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protein phosphatase 1L isoform 1 [Homo sapiens]
protein phosphatase 1L isoform 1 [Homo sapiens]
gi|63003905|ref|NP_640338.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000319053	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000696017	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 7, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15840476, 19841300, 22949429 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000319053

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jul 20, 2022)

germline

clinical testing

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

Citation Link,

SCV000696017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 7, 2016)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

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

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, Amin AS, Nannenberg EA, Ware JS, Whiffin N, Mazzarotto F, Škorić-Milosavljević D, Krijger C, Arbelo E, Babuty D, Barajas-Martinez H, Beckmann BM, Bézieau S, Bos JM, Breckpot J, Campuzano O, Castelletti S, et al.

Genet Med. 2021 Jan;23(1):47-58. doi: 10.1038/s41436-020-00946-5. Epub 2020 Sep 7.

PubMed [citation]

PMID:: 32893267
PMCID:: PMC7790744

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 (4)

Details of each submission

From Ambry Genetics, SCV000319053.7

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

Description

The p.Y427S variant (also known as c.1280A>C), located in coding exon 6 of the KCNH2 gene, results from an A to C substitution at nucleotide position 1280. The tyrosine at codon 427 is replaced by serine, an amino acid with dissimilar properties. This alteration is located in the S1/S2 transmembrane domain of HERG and has been detected in individuals with long QT syndrome (Kapa S et al. Circulation. 2009;120:1752-1760; Walsh R et al. Genet Med, 2021 01;23:47-58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696017.1

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

Description

Variant summary: The KCNH2 c.1280A>C (p.Tyr427Ser) variant involves the alteration of a highly conserved nucleotide and is located in the ion transport domain at S1-S4 transmembrane region (InterPro, Itoh_2016). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 125938 control chromosomes, including the large and broad populations from ExAC. This variant has been reported as a pathogenic variant in literature found in at least two LQTS families; and in one family, the variant was found to be paternally inherited (Tester_2005, Kapa_2009, Giudicessi_2012, Itoh_2010, Itoh_2016). Other missense variants such as p.Tyr427His (PMIDs: 16414944, 16922724, and 22581653) and p.Tyr427Cys (PMIDs: 19716085 and 22581653) have also been reported in this codon, indicating that the codon is in a mutational hot-spot. One clinical diagnostic laboratory has classified this variant as likely pathogenic. Taken together, this variant is classified as Likely Pathogenic.

#	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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