ANK2 NM_001148.4 exon 45 p.Arg3906Trp (c.11716C>T): This variant has been reported in the literature in at least 7 individuals with syncope or clinical features of Long QT syndrome (Mohler 2004 PMID:15178757, Sherman 2005 PMID:16253912, Lieve 2013 PMID:2361430) as well as 1 infant with sudden death (Methner 2016 PMID:27435932). However, this variant is present in 0.1% (233/126380) of European alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912706). This variant is present in ClinVar (Variation ID:18059). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies using mouse cardiomyocytes have shown that this variant may impact the protein, potentially affecting cytoplasmic calcium release events and contraction rates, and may cause a loss of function (Mohler 2007 PMID:17242276). However, further studies are needed to understand its impact. In summary, due to conflicting evidence for this variant, the clinical significance of this variant is uncertain.
ClinVar Genomic variation as it relates to human health
NM_001148.6(ANK2):c.11716C>T (p.Arg3906Trp)
Germline
Classification
Help
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.
(13)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(3); Likely benign(4)
Uncertain significance(2); Benign(3); Likely benign(4)
13
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001148.6(ANK2):c.11716C>T (p.Arg3906Trp)
Variation ID: 18059 Accession: VCV000018059.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q26 4: 113373306 (GRCh38) [ NCBI UCSC ] 4: 114294462 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001148.6:c.11716C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001139.3:p.Arg3906Trp missense NM_001127493.3:c.5434C>T NP_001120965.1:p.Arg1812Trp missense NM_001354225.2:c.5473C>T NP_001341154.1:p.Arg1825Trp missense NM_001354228.2:c.5455C>T NP_001341157.1:p.Arg1819Trp missense NM_001354230.2:c.5440C>T NP_001341159.1:p.Arg1814Trp missense NM_001354231.2:c.5596C>T NP_001341160.1:p.Arg1866Trp missense NM_001354232.2:c.5590C>T NP_001341161.1:p.Arg1864Trp missense NM_001354235.2:c.5551C>T NP_001341164.1:p.Arg1851Trp missense NM_001354236.2:c.5359C>T NP_001341165.1:p.Arg1787Trp missense NM_001354237.2:c.5539C>T NP_001341166.1:p.Arg1847Trp missense NM_001354239.2:c.5524C>T NP_001341168.1:p.Arg1842Trp missense NM_001354240.2:c.5506C>T NP_001341169.1:p.Arg1836Trp missense NM_001354241.2:c.5506C>T NP_001341170.1:p.Arg1836Trp missense NM_001354242.2:c.5503C>T NP_001341171.1:p.Arg1835Trp missense NM_001354243.2:c.5491C>T NP_001341172.1:p.Arg1831Trp missense NM_001354244.2:c.5488C>T NP_001341173.1:p.Arg1830Trp missense NM_001354245.2:c.5299C>T NP_001341174.1:p.Arg1767Trp missense NM_001354246.2:c.5458C>T NP_001341175.1:p.Arg1820Trp missense NM_001354249.2:c.5275C>T NP_001341178.1:p.Arg1759Trp missense NM_001354252.2:c.5431C>T NP_001341181.1:p.Arg1811Trp missense NM_001354253.2:c.5236C>T NP_001341182.1:p.Arg1746Trp missense NM_001354254.2:c.5410C>T NP_001341183.1:p.Arg1804Trp missense NM_001354255.2:c.5398C>T NP_001341184.1:p.Arg1800Trp missense NM_001354256.2:c.5395C>T NP_001341185.1:p.Arg1799Trp missense NM_001354257.2:c.5200C>T NP_001341186.1:p.Arg1734Trp missense NM_001354258.2:c.5362C>T NP_001341187.1:p.Arg1788Trp missense NM_001354260.2:c.5176C>T NP_001341189.1:p.Arg1726Trp missense NM_001354261.2:c.5320C>T NP_001341190.1:p.Arg1774Trp missense NM_001354262.2:c.5299C>T NP_001341191.1:p.Arg1767Trp missense NM_001354264.2:c.5296C>T NP_001341193.1:p.Arg1766Trp missense NM_001354265.2:c.5436+133C>T intron variant NM_001354266.2:c.5275C>T NP_001341195.1:p.Arg1759Trp missense NM_001354267.2:c.5275C>T NP_001341196.1:p.Arg1759Trp missense NM_001354268.2:c.5263C>T NP_001341197.1:p.Arg1755Trp missense NM_001354269.3:c.5248C>T NP_001341198.1:p.Arg1750Trp missense NM_001354270.2:c.5236C>T NP_001341199.1:p.Arg1746Trp missense NM_001354271.2:c.5176C>T NP_001341200.1:p.Arg1726Trp missense NM_001354272.2:c.5310+133C>T intron variant NM_001354273.2:c.5161C>T NP_001341202.1:p.Arg1721Trp missense NM_001354274.2:c.5298+133C>T intron variant NM_001354275.2:c.5277+133C>T intron variant NM_001354276.2:c.5253+133C>T intron variant NM_001354277.2:c.5055+133C>T intron variant NM_001354278.2:c.2989C>T NP_001341207.1:p.Arg997Trp missense NM_001354279.2:c.3025C>T NP_001341208.1:p.Arg1009Trp missense NM_001354280.2:c.3010C>T NP_001341209.1:p.Arg1004Trp missense NM_001354281.2:c.2989C>T NP_001341210.1:p.Arg997Trp missense NM_001354282.2:c.3003+133C>T intron variant NM_001386142.1:c.11482C>T NP_001373071.1:p.Arg3828Trp missense NM_001386143.1:c.5491C>T NP_001373072.1:p.Arg1831Trp missense NM_001386144.1:c.5599C>T NP_001373073.1:p.Arg1867Trp missense NM_001386146.1:c.5335C>T NP_001373075.1:p.Arg1779Trp missense NM_001386147.1:c.5287C>T NP_001373076.1:p.Arg1763Trp missense NM_001386148.2:c.5446C>T NP_001373077.1:p.Arg1816Trp missense NM_001386149.1:c.5242C>T NP_001373078.1:p.Arg1748Trp missense NM_001386150.1:c.5335C>T NP_001373079.1:p.Arg1779Trp missense NM_001386151.1:c.5269C>T NP_001373080.1:p.Arg1757Trp missense NM_001386152.1:c.5412+3501C>T intron variant NM_001386153.1:c.5242C>T NP_001373082.1:p.Arg1748Trp missense NM_001386154.1:c.5227C>T NP_001373083.1:p.Arg1743Trp missense NM_001386156.1:c.5200C>T NP_001373085.1:p.Arg1734Trp missense NM_001386157.1:c.5077C>T NP_001373086.1:p.Arg1693Trp missense NM_001386158.1:c.4978C>T NP_001373087.1:p.Arg1660Trp missense NM_001386160.1:c.5305C>T NP_001373089.1:p.Arg1769Trp missense NM_001386161.1:c.5395C>T NP_001373090.1:p.Arg1799Trp missense NM_001386162.1:c.5253+133C>T intron variant NM_001386166.1:c.8116C>T NP_001373095.1:p.Arg2706Trp missense NM_001386167.1:c.1954C>T NP_001373096.1:p.Arg652Trp missense NM_001386174.1:c.11950C>T NP_001373103.1:p.Arg3984Trp missense NM_001386175.1:c.11926C>T NP_001373104.1:p.Arg3976Trp missense NM_001386186.2:c.5446C>T NP_001373115.1:p.Arg1816Trp missense NM_001386187.2:c.5326C>T NP_001373116.1:p.Arg1776Trp missense NM_020977.5:c.5461C>T NP_066187.2:p.Arg1821Trp missense NC_000004.12:g.113373306C>T NC_000004.11:g.114294462C>T NG_009006.2:g.560224C>T LRG_327:g.560224C>T LRG_327t1:c.11716C>T Q01484:p.Arg3906Trp - Protein change
- R1788W, R1812W, R1821W, R3906W, R1009W, R1721W, R1734W, R1746W, R1755W, R1759W, R1836W, R1004W, R1750W, R1774W, R1800W, R1811W, R1820W, R1831W, R1835W, R1847W, R1851W, R1864W, R1766W, R1767W, R1799W, R1804W, R1814W, R1830W, R1866W, R997W, R1726W, R1787W, R1819W, R1825W, R1842W, R1660W, R1693W, R1743W, R1748W, R1757W, R1763W, R1769W, R1776W, R1779W, R1816W, R1867W, R2706W, R3828W, R3976W, R3984W, R652W
- Other names
-
p.R3906W:CGG>TGG
- Canonical SPDI
- NC_000004.12:113373305:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00060 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00078
The Genome Aggregation Database (gnomAD) 0.00094
The Genome Aggregation Database (gnomAD), exomes 0.00102
Trans-Omics for Precision Medicine (TOPMed) 0.00104
Exome Aggregation Consortium (ExAC) 0.00112
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ANK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2683 | 3270 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jun 15, 2004 | RCV000019676.35 | |
| Benign (1) |
criteria provided, single submitter
|
Apr 8, 2019 | RCV000211890.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 27, 2015 | RCV000234999.9 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2023 | RCV000474063.34 | |
| Benign (1) |
criteria provided, single submitter
|
Mar 16, 2022 | RCV000620379.11 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 17, 2017 | RCV000852983.9 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV001082560.13 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2021 | RCV001145853.13 | |
| Likely benign (2) |
criteria provided, single submitter
|
Jun 24, 2013 | RCV001841250.10 | |
|
ANK2-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Feb 18, 2023 | RCV003904850.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050754.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 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: 1
|
|
|
Likely benign
(Mar 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995732.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia, ankyrin-B-related
Cardiac arrhythmia, ankyrin-B-related
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920137.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
ANK2 NM_001148.4 exon 45 p.Arg3906Trp (c.11716C>T): This variant has been reported in the literature in at least 7 individuals with syncope or clinical features of … (more)
ANK2 NM_001148.4 exon 45 p.Arg3906Trp (c.11716C>T): This variant has been reported in the literature in at least 7 individuals with syncope or clinical features of Long QT syndrome (Mohler 2004 PMID:15178757, Sherman 2005 PMID:16253912, Lieve 2013 PMID:2361430) as well as 1 infant with sudden death (Methner 2016 PMID:27435932). However, this variant is present in 0.1% (233/126380) of European alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912706). This variant is present in ClinVar (Variation ID:18059). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies using mouse cardiomyocytes have shown that this variant may impact the protein, potentially affecting cytoplasmic calcium release events and contraction rates, and may cause a loss of function (Mohler 2007 PMID:17242276). However, further studies are needed to understand its impact. In summary, due to conflicting evidence for this variant, the clinical significance of this variant is uncertain. (less)
|
|
|
Likely benign
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000223217.14
First in ClinVar: May 23, 2015 Last updated: Jun 17, 2023 |
Comment:
See Variant Classification Assertion Criteria.
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000557197.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Mar 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737448.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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)
|
|
|
Benign
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001154266.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
ANK2: BS1, BS2
Number of individuals with the variant: 6
|
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia, ankyrin-B-related
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001306553.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Benign
(Apr 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363525.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ANK2 c.11716C>T (p.Arg3906Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ANK2 c.11716C>T (p.Arg3906Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 276816 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 270 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome (LQTS) phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Mohler et al (2004) originally reported the variant in one LQTS proband from one family without segregation analysis performed, and also, the proband of another family with unknown/uncertain LQTS phenotype and her father who was asymptomatic. This study predates the emergence of large control population datasets. Subsequently, c.11716C>T has been reported in the literature in individuals affected with LQTS and hypertrophic cardiomyopathy and also, in a stillbirth case (Sahlin_2019, Lopes_2015, Sherman_2015, Lieve_2013, Ng_2013). A co-occurrence with a pathogenic variant causative of LQT syndrome has been reported at our laboratory (KCNQ1, c.1663C>T, p.Arg555Cys), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to abolish ability of ankyrin-B to restore abnormal calcium dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP3R in mouse cardiomyocytes (Mohler_2004). However, it is not evident how these outcomes correlate to incidence of disease in human. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x), uncertain significance (1x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Pathogenic
(Jun 15, 2004)
|
no assertion criteria provided
Method: literature only
|
LONG QT SYNDROME 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039974.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 unrelated probands with long QT syndrome (LQT4; 600919), Mohler et al. (2004) identified a 5336C-T transition in exon 45 of the ANK2 gene, … (more)
In 2 unrelated probands with long QT syndrome (LQT4; 600919), Mohler et al. (2004) identified a 5336C-T transition in exon 45 of the ANK2 gene, resulting in an arg1788-to-trp (R1788W) substitution. One proband was a 37-year-old Caucasian female from the United States. She presented with syncope (originally treated as a seizure) at age 12 years. This woman subsequently had multiple episodes of syncope associated with sleep, and torsades de pointes ventricular tachycardia was documented. Beta-blocker therapy failed to eliminate symptoms and she was treated with an implantable cardiac defibrillator. ECGs revealed a heart rate of 60 beats per minute, prominent T-U waves, and prolongation of the QT interval with a QTc of 530 msec. The proband's son had also been diagnosed with long QT syndrome. The second proband, heterozygous for the R1788W mutation, was a Caucasian female from Europe with multiple episodes of exercise-associated syncope. She presented with supraventricular and ventricular tachycardias that were reproducibly elicited by exercise tests. The patient had normal QTc at rest (430 msec), but prolongation of 470 msec was observed after a syncopal episode. The woman was successfully treated with beta blockers; however, exercise-induced nonsustained supraventricular and ventricular arrhythmias persisted. The father of the proband carried the mutation with QTc of 430 msec and a heart rate of 67 beats per minute. The R1788W mutation was not identified in 280 DNA samples obtained from individuals with normal ECG. (less)
|
|
|
Pathogenic
(Mar 27, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Death in infancy
Affected status: yes
Allele origin:
unknown
|
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences
Study: HCIFS-Postmortem genetic screening project
Accession: SCV000263109.1 First in ClinVar: Jul 15, 2016 Last updated: Jul 15, 2016 |
Clinical Features:
Death in infancy (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: African American
Tissue: Blood
|
|
|
Likely benign
(Feb 18, 2023)
|
no assertion criteria provided
Method: clinical testing
|
ANK2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004726408.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089871.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
See Variant Classification Assertion Criteria.
Comment:
This alteration is classified as 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.
Comment:
ANK2: BS1, BS2
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Variant summary: ANK2 c.11716C>T (p.Arg3906Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 276816 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 270 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome (LQTS) phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Mohler et al (2004) originally reported the variant in one LQTS proband from one family without segregation analysis performed, and also, the proband of another family with unknown/uncertain LQTS phenotype and her father who was asymptomatic. This study predates the emergence of large control population datasets. Subsequently, c.11716C>T has been reported in the literature in individuals affected with LQTS and hypertrophic cardiomyopathy and also, in a stillbirth case (Sahlin_2019, Lopes_2015, Sherman_2015, Lieve_2013, Ng_2013). A co-occurrence with a pathogenic variant causative of LQT syndrome has been reported at our laboratory (KCNQ1, c.1663C>T, p.Arg555Cys), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to abolish ability of ankyrin-B to restore abnormal calcium dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP3R in mouse cardiomyocytes (Mohler_2004). However, it is not evident how these outcomes correlate to incidence of disease in human. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x), uncertain significance (1x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
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. |
Comment:
ANK2 NM_001148.4 exon 45 p.Arg3906Trp (c.11716C>T): This variant has been reported in the literature in at least 7 individuals with syncope or clinical features of Long QT syndrome (Mohler 2004 PMID:15178757, Sherman 2005 PMID:16253912, Lieve 2013 PMID:2361430) as well as 1 infant with sudden death (Methner 2016 PMID:27435932). However, this variant is present in 0.1% (233/126380) of European alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912706). This variant is present in ClinVar (Variation ID:18059). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies using mouse cardiomyocytes have shown that this variant may impact the protein, potentially affecting cytoplasmic calcium release events and contraction rates, and may cause a loss of function (Mohler 2007 PMID:17242276). However, further studies are needed to understand its impact. In summary, due to conflicting evidence for this variant, the clinical significance of this variant is uncertain.
Comment:
See Variant Classification Assertion Criteria.
Comment:
This alteration is classified as 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.
Comment:
ANK2: BS1, BS2
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Variant summary: ANK2 c.11716C>T (p.Arg3906Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 276816 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 270 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome (LQTS) phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Mohler et al (2004) originally reported the variant in one LQTS proband from one family without segregation analysis performed, and also, the proband of another family with unknown/uncertain LQTS phenotype and her father who was asymptomatic. This study predates the emergence of large control population datasets. Subsequently, c.11716C>T has been reported in the literature in individuals affected with LQTS and hypertrophic cardiomyopathy and also, in a stillbirth case (Sahlin_2019, Lopes_2015, Sherman_2015, Lieve_2013, Ng_2013). A co-occurrence with a pathogenic variant causative of LQT syndrome has been reported at our laboratory (KCNQ1, c.1663C>T, p.Arg555Cys), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to abolish ability of ankyrin-B to restore abnormal calcium dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP3R in mouse cardiomyocytes (Mohler_2004). However, it is not evident how these outcomes correlate to incidence of disease in human. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x), uncertain significance (1x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth. | Sahlin E | PloS one | 2019 | PMID: 30615648 |
| Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. | Methner DN | Genome research | 2016 | PMID: 27435932 |
| Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases. | Tšuiko O | Human reproduction (Oxford, England) | 2016 | PMID: 27301361 |
| Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
| Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
| Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
| Obscurin targets ankyrin-B and protein phosphatase 2A to the cardiac M-line. | Cunha SR | The Journal of biological chemistry | 2008 | PMID: 18782775 |
| Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects. | Sherman J | Heart rhythm | 2005 | PMID: 16253912 |
| 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 |
| Isoform specificity among ankyrins. An amphipathic alpha-helix in the divergent regulatory domain of ankyrin-b interacts with the molecular co-chaperone Hdj1/Hsp40. | Mohler PJ | The Journal of biological chemistry | 2004 | PMID: 15075330 |
Text-mined citations for rs121912706 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.