ClinVar Genomic variation as it relates to human health
NM_001148.6(ANK2):c.4373A>G (p.Glu1458Gly)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(5); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001148.6(ANK2):c.4373A>G (p.Glu1458Gly)
Variation ID: 18056 Accession: VCV000018056.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q26 4: 113348277 (GRCh38) [ NCBI UCSC ] 4: 114269433 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 1, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001148.6:c.4373A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001139.3:p.Glu1458Gly missense NM_001127493.3:c.4346A>G NP_001120965.1:p.Glu1449Gly missense NM_001354225.2:c.4385A>G NP_001341154.1:p.Glu1462Gly missense NM_001354228.2:c.4274A>G NP_001341157.1:p.Glu1425Gly missense NM_001354230.2:c.4352A>G NP_001341159.1:p.Glu1451Gly missense NM_001354231.2:c.4415A>G NP_001341160.1:p.Glu1472Gly missense NM_001354232.2:c.4409A>G NP_001341161.1:p.Glu1470Gly missense NM_001354235.2:c.4370A>G NP_001341164.1:p.Glu1457Gly missense NM_001354236.2:c.4271A>G NP_001341165.1:p.Glu1424Gly missense NM_001354237.2:c.4451A>G NP_001341166.1:p.Glu1484Gly missense NM_001354239.2:c.4343A>G NP_001341168.1:p.Glu1448Gly missense NM_001354240.2:c.4418A>G NP_001341169.1:p.Glu1473Gly missense NM_001354241.2:c.4418A>G NP_001341170.1:p.Glu1473Gly missense NM_001354242.2:c.4415A>G NP_001341171.1:p.Glu1472Gly missense NM_001354243.2:c.4310A>G NP_001341172.1:p.Glu1437Gly missense NM_001354244.2:c.4307A>G NP_001341173.1:p.Glu1436Gly missense NM_001354245.2:c.4211A>G NP_001341174.1:p.Glu1404Gly missense NM_001354246.2:c.4370A>G NP_001341175.1:p.Glu1457Gly missense NM_001354249.2:c.4187A>G NP_001341178.1:p.Glu1396Gly missense NM_001354252.2:c.4343A>G NP_001341181.1:p.Glu1448Gly missense NM_001354253.2:c.4148A>G NP_001341182.1:p.Glu1383Gly missense NM_001354254.2:c.4322A>G NP_001341183.1:p.Glu1441Gly missense NM_001354255.2:c.4310A>G NP_001341184.1:p.Glu1437Gly missense NM_001354256.2:c.4307A>G NP_001341185.1:p.Glu1436Gly missense NM_001354257.2:c.4112A>G NP_001341186.1:p.Glu1371Gly missense NM_001354258.2:c.4274A>G NP_001341187.1:p.Glu1425Gly missense NM_001354260.2:c.4088A>G NP_001341189.1:p.Glu1363Gly missense NM_001354261.2:c.4232A>G NP_001341190.1:p.Glu1411Gly missense NM_001354262.2:c.4211A>G NP_001341191.1:p.Glu1404Gly missense NM_001354264.2:c.4208A>G NP_001341193.1:p.Glu1403Gly missense NM_001354265.2:c.4370A>G NP_001341194.1:p.Glu1457Gly missense NM_001354266.2:c.4187A>G NP_001341195.1:p.Glu1396Gly missense NM_001354267.2:c.4187A>G NP_001341196.1:p.Glu1396Gly missense NM_001354268.2:c.4175A>G NP_001341197.1:p.Glu1392Gly missense NM_001354269.3:c.4160A>G NP_001341198.1:p.Glu1387Gly missense NM_001354270.2:c.4148A>G NP_001341199.1:p.Glu1383Gly missense NM_001354271.2:c.4088A>G NP_001341200.1:p.Glu1363Gly missense NM_001354272.2:c.4244A>G NP_001341201.1:p.Glu1415Gly missense NM_001354273.2:c.4073A>G NP_001341202.1:p.Glu1358Gly missense NM_001354274.2:c.4171-1951A>G intron variant NM_001354275.2:c.4211A>G NP_001341204.1:p.Glu1404Gly missense NM_001354276.2:c.4187A>G NP_001341205.1:p.Glu1396Gly missense NM_001354277.2:c.3989A>G NP_001341206.1:p.Glu1330Gly missense NM_001354278.2:c.1901A>G NP_001341207.1:p.Glu634Gly missense NM_001354279.2:c.1937A>G NP_001341208.1:p.Glu646Gly missense NM_001354280.2:c.1922A>G NP_001341209.1:p.Glu641Gly missense NM_001354281.2:c.1901A>G NP_001341210.1:p.Glu634Gly missense NM_001354282.2:c.1937A>G NP_001341211.1:p.Glu646Gly missense NM_001386142.1:c.4171-1951A>G intron variant NM_001386143.1:c.4310A>G NP_001373072.1:p.Glu1437Gly missense NM_001386144.1:c.4418A>G NP_001373073.1:p.Glu1473Gly missense NM_001386146.1:c.4186-1951A>G intron variant NM_001386147.1:c.4231-1951A>G intron variant NM_001386148.2:c.4358A>G NP_001373077.1:p.Glu1453Gly missense NM_001386149.1:c.4186-1951A>G intron variant NM_001386150.1:c.4186-1951A>G intron variant NM_001386151.1:c.4088A>G NP_001373080.1:p.Glu1363Gly missense NM_001386152.1:c.4430A>G NP_001373081.1:p.Glu1477Gly missense NM_001386153.1:c.4186-1951A>G intron variant NM_001386154.1:c.4171-1951A>G intron variant NM_001386156.1:c.4112A>G NP_001373085.1:p.Glu1371Gly missense NM_001386157.1:c.3989A>G NP_001373086.1:p.Glu1330Gly missense NM_001386158.1:c.3890A>G NP_001373087.1:p.Glu1297Gly missense NM_001386160.1:c.4217A>G NP_001373089.1:p.Glu1406Gly missense NM_001386161.1:c.4307A>G NP_001373090.1:p.Glu1436Gly missense NM_001386162.1:c.4187A>G NP_001373091.1:p.Glu1396Gly missense NM_001386166.1:c.773A>G NP_001373095.1:p.Glu258Gly missense NM_001386167.1:c.773A>G NP_001373096.1:p.Glu258Gly missense NM_001386174.1:c.4514A>G NP_001373103.1:p.Glu1505Gly missense NM_001386175.1:c.4490A>G NP_001373104.1:p.Glu1497Gly missense NM_001386186.2:c.4358A>G NP_001373115.1:p.Glu1453Gly missense NM_001386187.2:c.4238A>G NP_001373116.1:p.Glu1413Gly missense NM_020977.5:c.4373A>G NP_066187.2:p.Glu1458Gly missense NC_000004.12:g.113348277A>G NC_000004.11:g.114269433A>G NG_009006.2:g.535195A>G LRG_327:g.535195A>G LRG_327t1:c.4373A>G Q01484:p.Glu1458Gly - Protein change
- E1425G, E1449G, E1458G, E1403G, E1436G, E1451G, E1457G, E1470G, E634G, E1404G, E1424G, E1437G, E1448G, E1472G, E1473G, E1330G, E1371G, E1411G, E1415G, E1441G, E1484G, E646G, E1358G, E1363G, E1383G, E1387G, E1392G, E1396G, E1462G, E641G, E1297G, E1406G, E1413G, E1453G, E1477G, E1497G, E1505G, E258G
- Other names
- p.E1458G:GAA>GGA
- Canonical SPDI
- NC_000004.12:113348276:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00042
The Genome Aggregation Database (gnomAD), exomes 0.00055
The Genome Aggregation Database (gnomAD) 0.00085
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00121
1000 Genomes Project 30x 0.00125
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ANK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2585 | 3156 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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no classifications from unflagged records (1) |
no classifications from unflagged records
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Jan 19, 2024 | RCV000019672.28 | |
Uncertain significance (3) |
criteria provided, single submitter
|
Feb 16, 2024 | RCV000019673.36 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV000171737.10 | |
Likely benign (1) |
criteria provided, single submitter
|
Nov 4, 2021 | RCV000244762.6 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 1, 2018 | RCV001002092.8 | |
Uncertain significance (1) |
criteria provided, single submitter
|
- | RCV000845369.3 | |
not provided (1) |
no classification provided
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- | RCV000058356.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2023 | RCV000170702.13 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Long QT syndrome
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050744.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
|
Number of individuals with the variant: 2
|
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Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Conduction disorder of the heart
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987427.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
|
|
Uncertain significance
(Oct 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159938.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The ANK2 c.4373A>G; p.Glu1458Gly variant (rs72544141), also known as p.Glu1425Gly, is reported in the literature in individuals affected with Long QT syndrome, sinus node dysfunction, … (more)
The ANK2 c.4373A>G; p.Glu1458Gly variant (rs72544141), also known as p.Glu1425Gly, is reported in the literature in individuals affected with Long QT syndrome, sinus node dysfunction, arrhythmia, sudden unexplained death, and hypertrophic cardiomyopathy (Hertz 2016, Le Scouarnec 2008, Lin 2017. Lopes 2013, Mohler 2003, Neubauer 2017). In one large family, this variant segregated with long QT syndrome and sinus node dysfunction in more than 20 affected individuals and was not observed in any unaffected individuals (Le Scouarnec 2008, Mohler 2003). However, this variant was also observed in a healthy individual with normal QT interval (Mohler 2004), and it was not significantly associated with longer QT interval in a large Dutch cohort (Ghouse 2015). Further, the p.Glu1458Gly variant is found in the Latino population with an overall allele frequency of 0.11% (38/24226 alleles, including one homozygote) in the Genome Aggregation Database, and this population frequency exceeds the estimated prevalence of Long QT syndrome at 1 in 2000 (Lin 2017). In mouse cardiomyocytes lacking one copy of ANK2, transfection of the p.Glu1458Gly variant fails to rescue decreased spontaneous contraction rate to the same extent as wildtype protein (Mohler 2003, Mohler 2007). The glutamate at codon 1458 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the p.Glu1458Gly variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Hertz CL et al. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Hum Genet. 2016 Jun;24(6):817-22. Le Scouarnec S et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15617-22. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6). Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Mohler PJ et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. Mohler PJ et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9. Mohler PJ et al. Defining the cellular phenotype of ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation. 2007 Jan 30;115(4):432-41. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 Apr;25(4):404-409. " (less)
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Uncertain significance
(May 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503360.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
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Uncertain significance
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000223255.20
First in ClinVar: May 23, 2015 Last updated: Nov 25, 2023 |
Comment:
Reported in several individuals with sudden death/SIDS (PMID: 26350513, 27930701, 29247119, 28074886) and in association with HCM (PMID: 23396983, 25351510), although additional cardiogenetic variants were … (more)
Reported in several individuals with sudden death/SIDS (PMID: 26350513, 27930701, 29247119, 28074886) and in association with HCM (PMID: 23396983, 25351510), although additional cardiogenetic variants were identified in some of these probands; Reported in several individuals without a known history of cardiovascular disease (PMID: 23861362, 26159999, 28654958, 29431110); Identified as secondary finding in a cohort of patients with intellectual disability or developmental delay referred for WES/WGS who was reported to have a clinical diagnosis of HCM and arrhythmia (PMID: 29790872); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated this variant results in abnormal Ca2+ signaling in mouse cardiomyocytes, and mice heterozygous for this variant had a high incidence of sudden death after exercise and exposure to epinephrine (PMID: 12571597, 17242276); This variant is associated with the following publications: (PMID: 17242276, 23396983, 26159999, 15178757, 7485162, 29247119, 28880023, 27930701, 28654958, 28074886, 18832177, 26220970, 26350513, 19394342, 29431110, 20724725, 22581653, 28988457, 25351510, 32164423, 29198934, 35990955, 12571597, 29790872, 23861362) (less)
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Likely benign
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000286249.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
|
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Likely benign
(Nov 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000318832.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Feb 16, 2024)
|
criteria provided, single submitter
Method: research
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Cardiac arrhythmia, ankyrin-B-related
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584065.3 First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024 |
Number of individuals with the variant: 1
|
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089876.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12571597;PMID:15178757;PMID:18832177). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12571597;PMID:15178757;PMID:18832177). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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Pathogenic
(Jun 15, 2004)
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Flagged submission
flagged submission
Method: literature only
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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LONG QT SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039970.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a large French kindred with autosomal dominant type 4 long QT syndrome (600919), Mohler et al. (2003) demonstrated that the underlying defect is a … (more)
In a large French kindred with autosomal dominant type 4 long QT syndrome (600919), Mohler et al. (2003) demonstrated that the underlying defect is a glu1425-to-gly (E1425G) missense mutation in ankyrin-B. The amino acid substitution was the result of an A-to-G transition at nucleotide position 4274 in exon 36 of the ANK2 gene. Further studies reported by Mohler et al. (2004) expanded the phenotype associated with this mutation (see 600919). In a screening of 664 patients for mutations in the ANK2 gene, a Caucasian female was found to carry the E1425G mutation. She was clinically unaffected and, in contrast to previously identified E1425G patients (Mohler et al., 2003), had a normal QTc of 410 msec with a heart rate of 60 beats per minute. The proband's 67-year-old mother was a carrier of the E1425G variant with slightly elevated QTc (430-450 msec) and moderately low heart rate (63 beats per minute). Three sibs of the proband died young of sudden death at 25, 17, and 15 years of age. The 25-year-old died while winning a prize. The 17-year-old died in the shower and had previously experienced syncopal episodes associated with athletics. The 15-year-old died getting out of the pool after swimming. The E1425G mutation was not observed in 550 control individuals. It was the only SSCP variant identified within the ankyrin-B spectrin-binding domain (exons 24-36). (less)
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Pathogenic
(Jun 15, 2004)
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Flagged submission
flagged submission
Method: literature only
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039971.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a large French kindred with autosomal dominant type 4 long QT syndrome (600919), Mohler et al. (2003) demonstrated that the underlying defect is a … (more)
In a large French kindred with autosomal dominant type 4 long QT syndrome (600919), Mohler et al. (2003) demonstrated that the underlying defect is a glu1425-to-gly (E1425G) missense mutation in ankyrin-B. The amino acid substitution was the result of an A-to-G transition at nucleotide position 4274 in exon 36 of the ANK2 gene. Further studies reported by Mohler et al. (2004) expanded the phenotype associated with this mutation (see 600919). In a screening of 664 patients for mutations in the ANK2 gene, a Caucasian female was found to carry the E1425G mutation. She was clinically unaffected and, in contrast to previously identified E1425G patients (Mohler et al., 2003), had a normal QTc of 410 msec with a heart rate of 60 beats per minute. The proband's 67-year-old mother was a carrier of the E1425G variant with slightly elevated QTc (430-450 msec) and moderately low heart rate (63 beats per minute). Three sibs of the proband died young of sudden death at 25, 17, and 15 years of age. The 25-year-old died while winning a prize. The 17-year-old died in the shower and had previously experienced syncopal episodes associated with athletics. The 15-year-old died getting out of the pool after swimming. The E1425G mutation was not observed in 550 control individuals. It was the only SSCP variant identified within the ankyrin-B spectrin-binding domain (exons 24-36). (less)
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Likely pathogenic
(Dec 22, 2014)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Cardiac arrhythmia, ankyrin B-related
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245576.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
Comment:
The p.Glu1458Gly variant (also referred to as p.Glu1425Gly) has been identified in >20 affected members of a large kindred with autosomal dominant long QT syndrome … (more)
The p.Glu1458Gly variant (also referred to as p.Glu1425Gly) has been identified in >20 affected members of a large kindred with autosomal dominant long QT syndrome (Mohler 2003). It has been identified in an unaffected individual whose three siblings died suddenly at a young age (Mohler 2004). It has also been identified in 0.06% (41/67458) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72544141). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro and in vivo functional studies in mice provide some evidence that the p.Glu1458Gly variant may impact protein function (Mohler 2003, Mohler 2004, Le Scouarnec 2008). In p.Glu1458Gly variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The mutational constraint spectrum quantified from variation in 141,456 humans. | Karczewski KJ | Nature | 2020 | PMID: 32461654 |
Genomic sequencing identifies secondary findings in a cohort of parent study participants. | Thompson ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29790872 |
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. | Reuter MS | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2018 | PMID: 29431110 |
Re-evaluating pathogenicity of variants associated with the long QT syndrome. | Kaltman JR | Journal of cardiovascular electrophysiology | 2018 | PMID: 28988457 |
Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. | Lin Y | Circulation. Cardiovascular genetics | 2017 | PMID: 29247119 |
Using high-resolution variant frequencies to empower clinical genome interpretation. | Whiffin N | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28518168 |
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. | Neubauer J | European journal of human genetics : EJHG | 2017 | PMID: 28074886 |
Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. | Hertz CL | European journal of human genetics : EJHG | 2016 | PMID: 26350513 |
Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. | Ghouse J | European heart journal | 2015 | PMID: 26159999 |
Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. | Le Scouarnec S | Proceedings of the National Academy of Sciences of the United States of America | 2008 | PMID: 18832177 |
A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. | Mohler PJ | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15178757 |
Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. | Mohler PJ | Nature | 2003 | PMID: 12571597 |
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Text-mined citations for rs72544141 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.