ClinVar Genomic variation as it relates to human health
NM_001148.6(ANK2):c.7183A>C (p.Thr2395Pro)
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(4); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001148.6(ANK2):c.7183A>C (p.Thr2395Pro)
Variation ID: 457049 Accession: VCV000457049.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q26 4: 113355801 (GRCh38) [ NCBI UCSC ] 4: 114276957 (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 Oct 10, 2018 May 1, 2024 Jan 13, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- T2395P, T1195P, T2317P, T2434P, T2442P
- Other names
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- Canonical SPDI
- NC_000004.12:113355800:A:C
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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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00017
The Genome Aggregation Database (gnomAD), exomes 0.00018
Exome Aggregation Consortium (ExAC) 0.00019
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00027
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 |
2597 | 3171 | |
LOC126807137 | - | - | - | GRCh38 | - | 287 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2024 | RCV000537225.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2020 | RCV000786103.7 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 8, 2022 | RCV002377012.2 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 26, 2020 | RCV001264520.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 20, 2019 | RCV001256865.2 |
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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Uncertain significance
(Jun 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Conduction disorder of the heart
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433357.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Likely benign
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442715.1
First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Comment:
Variant summary: ANK2 c.7183A>C (p.Thr2395Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: ANK2 c.7183A>C (p.Thr2395Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250596 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 69 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.7183A>C has been reported in the literature in individuals affected with Long QT Syndrome, hypertrophic cardiomyopathy and adult-onset sudden cardiac death (Lopes_2013, Brion_2014, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. One co-occurrence with another pathogenic variant has been internally reported (SCN5A c.5443_5446delTCTG, p.Ser1815ThrfsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Jul 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001771942.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Observed in patients with LQTS and SCD in the published literature (Brion et al., 2014; Campuzano et al., 2017); Reported in ClinVar as a variant … (more)
Observed in patients with LQTS and SCD in the published literature (Brion et al., 2014; Campuzano et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 457049; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26220970, 28255936, 28988457, 24981977) (less)
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Uncertain significance
(Mar 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818594.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 13, 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
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Invitae
Accession: SCV000627663.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2395 of the ANK2 protein (p.Thr2395Pro). … (more)
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2395 of the ANK2 protein (p.Thr2395Pro). This variant is present in population databases (rs201693280, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ANK2-related conditions (PMID: 23396983, 24981977, 26220970, 28255936). ClinVar contains an entry for this variant (Variation ID: 457049). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. (less)
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Likely benign
(Jun 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002667138.2
First in ClinVar: Nov 29, 2022 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
(Mar 17, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924747.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
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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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Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance. | Iglesias M | Journal of clinical medicine | 2021 | PMID: 33919104 |
Re-evaluating pathogenicity of variants associated with the long QT syndrome. | Kaltman JR | Journal of cardiovascular electrophysiology | 2018 | PMID: 28988457 |
Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis. | Campuzano O | Sports medicine (Auckland, N.Z.) | 2017 | PMID: 28255936 |
High-throughput genetic characterization of a cohort of Brugada syndrome patients. | Di Resta C | Human molecular genetics | 2015 | PMID: 26220970 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Next generation sequencing challenges in the analysis of cardiac sudden death due to arrhythmogenic disorders. | Brion M | Electrophoresis | 2014 | PMID: 24981977 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
Text-mined citations for rs201693280 ...
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.