This variant is associated with the following publications: (PMID: 16253912, 23631430, 15178757, 31539150, 32164423, 23861362)
ClinVar Genomic variation as it relates to human health
NM_001148.6(ANK2):c.11231C>A (p.Thr3744Asn)
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.
(15)
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(4); Benign(1); Likely benign(7)
Uncertain significance(4); Benign(1); Likely benign(7)
15
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.11231C>A (p.Thr3744Asn)
Variation ID: 18057 Accession: VCV000018057.48
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q26 4: 113367764 (GRCh38) [ NCBI UCSC ] 4: 114288920 (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 Jun 4, 2015 Oct 20, 2024 Jan 3, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001148.6:c.11231C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001139.3:p.Thr3744Asn missense NM_001127493.3:c.4949C>A NP_001120965.1:p.Thr1650Asn missense NM_001354225.2:c.4988C>A NP_001341154.1:p.Thr1663Asn missense NM_001354228.2:c.4877C>A NP_001341157.1:p.Thr1626Asn missense NM_001354230.2:c.4955C>A NP_001341159.1:p.Thr1652Asn missense NM_001354231.2:c.5018C>A NP_001341160.1:p.Thr1673Asn missense NM_001354232.2:c.5012C>A NP_001341161.1:p.Thr1671Asn missense NM_001354235.2:c.4973C>A NP_001341164.1:p.Thr1658Asn missense NM_001354236.2:c.4874C>A NP_001341165.1:p.Thr1625Asn missense NM_001354237.2:c.5054C>A NP_001341166.1:p.Thr1685Asn missense NM_001354239.2:c.4946C>A NP_001341168.1:p.Thr1649Asn missense NM_001354240.2:c.5021C>A NP_001341169.1:p.Thr1674Asn missense NM_001354241.2:c.5021C>A NP_001341170.1:p.Thr1674Asn missense NM_001354242.2:c.5018C>A NP_001341171.1:p.Thr1673Asn missense NM_001354243.2:c.4913C>A NP_001341172.1:p.Thr1638Asn missense NM_001354244.2:c.4910C>A NP_001341173.1:p.Thr1637Asn missense NM_001354245.2:c.4814C>A NP_001341174.1:p.Thr1605Asn missense NM_001354246.2:c.4973C>A NP_001341175.1:p.Thr1658Asn missense NM_001354249.2:c.4790C>A NP_001341178.1:p.Thr1597Asn missense NM_001354252.2:c.4946C>A NP_001341181.1:p.Thr1649Asn missense NM_001354253.2:c.4751C>A NP_001341182.1:p.Thr1584Asn missense NM_001354254.2:c.4925C>A NP_001341183.1:p.Thr1642Asn missense NM_001354255.2:c.4913C>A NP_001341184.1:p.Thr1638Asn missense NM_001354256.2:c.4910C>A NP_001341185.1:p.Thr1637Asn missense NM_001354257.2:c.4715C>A NP_001341186.1:p.Thr1572Asn missense NM_001354258.2:c.4877C>A NP_001341187.1:p.Thr1626Asn missense NM_001354260.2:c.4691C>A NP_001341189.1:p.Thr1564Asn missense NM_001354261.2:c.4835C>A NP_001341190.1:p.Thr1612Asn missense NM_001354262.2:c.4814C>A NP_001341191.1:p.Thr1605Asn missense NM_001354264.2:c.4811C>A NP_001341193.1:p.Thr1604Asn missense NM_001354265.2:c.4973C>A NP_001341194.1:p.Thr1658Asn missense NM_001354266.2:c.4790C>A NP_001341195.1:p.Thr1597Asn missense NM_001354267.2:c.4790C>A NP_001341196.1:p.Thr1597Asn missense NM_001354268.2:c.4778C>A NP_001341197.1:p.Thr1593Asn missense NM_001354269.3:c.4763C>A NP_001341198.1:p.Thr1588Asn missense NM_001354270.2:c.4751C>A NP_001341199.1:p.Thr1584Asn missense NM_001354271.2:c.4691C>A NP_001341200.1:p.Thr1564Asn missense NM_001354272.2:c.4847C>A NP_001341201.1:p.Thr1616Asn missense NM_001354273.2:c.4676C>A NP_001341202.1:p.Thr1559Asn missense NM_001354274.2:c.4742C>A NP_001341203.1:p.Thr1581Asn missense NM_001354275.2:c.4814C>A NP_001341204.1:p.Thr1605Asn missense NM_001354276.2:c.4790C>A NP_001341205.1:p.Thr1597Asn missense NM_001354277.2:c.4592C>A NP_001341206.1:p.Thr1531Asn missense NM_001354278.2:c.2504C>A NP_001341207.1:p.Thr835Asn missense NM_001354279.2:c.2540C>A NP_001341208.1:p.Thr847Asn missense NM_001354280.2:c.2525C>A NP_001341209.1:p.Thr842Asn missense NM_001354281.2:c.2504C>A NP_001341210.1:p.Thr835Asn missense NM_001354282.2:c.2540C>A NP_001341211.1:p.Thr847Asn missense NM_001386142.1:c.10997C>A NP_001373071.1:p.Thr3666Asn missense NM_001386143.1:c.4913C>A NP_001373072.1:p.Thr1638Asn missense NM_001386144.1:c.5021C>A NP_001373073.1:p.Thr1674Asn missense NM_001386146.1:c.4757C>A NP_001373075.1:p.Thr1586Asn missense NM_001386147.1:c.4802C>A NP_001373076.1:p.Thr1601Asn missense NM_001386148.2:c.4961C>A NP_001373077.1:p.Thr1654Asn missense NM_001386149.1:c.4757C>A NP_001373078.1:p.Thr1586Asn missense NM_001386150.1:c.4757C>A NP_001373079.1:p.Thr1586Asn missense NM_001386151.1:c.4691C>A NP_001373080.1:p.Thr1564Asn missense NM_001386152.1:c.5033C>A NP_001373081.1:p.Thr1678Asn missense NM_001386153.1:c.4757C>A NP_001373082.1:p.Thr1586Asn missense NM_001386154.1:c.4742C>A NP_001373083.1:p.Thr1581Asn missense NM_001386156.1:c.4715C>A NP_001373085.1:p.Thr1572Asn missense NM_001386157.1:c.4592C>A NP_001373086.1:p.Thr1531Asn missense NM_001386158.1:c.4493C>A NP_001373087.1:p.Thr1498Asn missense NM_001386160.1:c.4820C>A NP_001373089.1:p.Thr1607Asn missense NM_001386161.1:c.4910C>A NP_001373090.1:p.Thr1637Asn missense NM_001386162.1:c.4790C>A NP_001373091.1:p.Thr1597Asn missense NM_001386166.1:c.7631C>A NP_001373095.1:p.Thr2544Asn missense NM_001386167.1:c.1376C>A NP_001373096.1:p.Thr459Asn missense NM_001386174.1:c.11372C>A NP_001373103.1:p.Thr3791Asn missense NM_001386175.1:c.11348C>A NP_001373104.1:p.Thr3783Asn missense NM_001386186.2:c.4961C>A NP_001373115.1:p.Thr1654Asn missense NM_001386187.2:c.4841C>A NP_001373116.1:p.Thr1614Asn missense NM_020977.5:c.4976C>A NP_066187.2:p.Thr1659Asn missense NC_000004.12:g.113367764C>A NC_000004.11:g.114288920C>A NG_009006.2:g.554682C>A LRG_327:g.554682C>A LRG_327t1:c.11231C>A Q01484:p.Thr3744Asn - Protein change
- T1626N, T1650N, T1659N, T3744N, T1581N, T1605N, T1625N, T1637N, T1663N, T1531N, T1612N, T1638N, T1642N, T1658N, T1685N, T1559N, T1588N, T1593N, T1604N, T1616N, T1652N, T1674N, T847N, T1564N, T1572N, T1584N, T1597N, T1649N, T1671N, T1673N, T835N, T842N, T1498N, T1586N, T1601N, T1607N, T1614N, T1654N, T1678N, T2544N, T3666N, T3783N, T3791N, T459N
- Other names
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p.T3744N:ACT>AAT
- Canonical SPDI
- NC_000004.12:113367763:C:A
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00062
The Genome Aggregation Database (gnomAD), exomes 0.00063
Trans-Omics for Precision Medicine (TOPMed) 0.00070
The Genome Aggregation Database (gnomAD) 0.00077
- 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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2021 | RCV000019674.41 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 3, 2024 | RCV000204635.21 | |
| Likely benign (2) |
criteria provided, single submitter
|
Nov 7, 2021 | RCV000223796.17 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 1, 2024 | RCV000723633.39 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 3, 2023 | RCV000618056.12 | |
| Likely benign (2) |
criteria provided, single submitter
|
Jun 24, 2013 | RCV001841248.10 |
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: SCV000050753.1 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
|
|
|
Uncertain significance
(Feb 25, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000263782.2
First in ClinVar: Feb 27, 2016 Last updated: May 26, 2018 |
Number of individuals with the variant: 1
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987420.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
|
|
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Likely benign
(May 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000223265.12
First in ClinVar: May 23, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 16253912, 23631430, 15178757, 31539150, 32164423, 23861362)
|
|
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Likely benign
(Dec 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049155.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
|
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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: SCV003920126.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler … (more)
ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler 2004 PMID:15178757, Lieve 2013 PMID:23631430). However, this variant is present in 0.1% (157/126452) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912705). This variant is present in ClinVar, with conflicting classifications of this variant (Variation ID:18057). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain. (less)
|
|
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Likely benign
(Mar 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737813.5
First in ClinVar: Apr 14, 2018 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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Benign
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001154264.21
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
ANK2: BS1, BS2
Number of individuals with the variant: 5
|
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Uncertain significance
(Aug 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230577.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
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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: SCV001304614.1
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)
|
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Likely benign
(Nov 07, 2021)
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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: SCV002041623.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
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Likely benign
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260737.9
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
|
|
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Uncertain significance
(Oct 12, 2015)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280047.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as a variant of unknown significance. This variant has been previously reported in two unrelated individuals with borderline prolonged QT intervals (Mohler P et at., 2004; due to alternative nomenclature, they report it as Thr1626Asn). One of the reported individuals had a daughter, also heterozygous for the variant, who died suddenly at age 19 with no prior cardiac symptoms. All other carriers of the variant in the two families were asymptomatic. This is a conservative amino acid change, resulting in the replacement of a threonine (polar) with an asparagine (polar). Threonine at this location is conserved across most mammalian species for which data is available with the exception of the mouse and x-tropicalis. In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” with a score of 0.951. In total, the variant has been seen in at least 12/6700 individuals from published controls and publicly available population datasets. This variant is listed in the NHLBI Exome Sequencing Project dataset, where it was found in 11 of 6503 genotyped individuals (2 of 2203 African Americans and 9 of 4300 European Americans), indicating that it may be a rare benign variant. Another variant affecting the same residue, T3744P, was also seen in 1 of 6503 genotyped individuals. This variant, T3744N, has been listed in dpSNP, but has not been documented in 1000 genomes. It was observed in 1 of 200 published control individuals of African American descent (Sherman J et al., 2005). (less)
Number of individuals with the variant: 3
|
|
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Pathogenic
(Jun 15, 2004)
|
no assertion criteria provided
Method: literature only
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CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039972.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 2 unrelated Caucasian probands from the United States with marginally elevated QTc and arrhythmia (600919), Mohler et al. (2004) identified a 4877C-A transversion in … (more)
In 2 unrelated Caucasian probands from the United States with marginally elevated QTc and arrhythmia (600919), Mohler et al. (2004) identified a 4877C-A transversion in exon 42 of the ANK2 gene, resulting in a thr1626-to-asn (T1626N) substitution. One proband was a 46-year-old female who had a QTc of 450 msec and had experienced syncope, but had a normal resting heart rate of 72 beats per minute. Her daughter was also heterozygous for the T1626N mutation and died of sudden death at age 19 years with no previous cardiac symptoms; QTc and heart rate data were not available. Two sibs, 2 sons, and the mother of the proband were also carriers of the mutation and had resting QTc in the normal range. At the time of report, these carriers were asymptomatic. The second proband was a 51-year-old male who displayed mildly elevated QTc (450 msec) with sinus arrhythmia (heart rate varying from 50 to 110 beats per minute). Two of his sibs with normal QTc were heterozygous for the T1626N mutation but asymptomatic at the time of report. The T1626N mutation was not observed in 550 control individuals. (less)
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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: SCV000089867.3
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)
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Comment:
Comment:
ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler 2004 PMID:15178757, Lieve 2013 PMID:23631430). However, this variant is present in 0.1% (157/126452) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912705). This variant is present in ClinVar, with conflicting classifications of this variant (Variation ID:18057). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
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 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:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as a variant of unknown significance. This variant has been previously reported in two unrelated individuals with borderline prolonged QT intervals (Mohler P et at., 2004; due to alternative nomenclature, they report it as Thr1626Asn). One of the reported individuals had a daughter, also heterozygous for the variant, who died suddenly at age 19 with no prior cardiac symptoms. All other carriers of the variant in the two families were asymptomatic. This is a conservative amino acid change, resulting in the replacement of a threonine (polar) with an asparagine (polar). Threonine at this location is conserved across most mammalian species for which data is available with the exception of the mouse and x-tropicalis. In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” with a score of 0.951. In total, the variant has been seen in at least 12/6700 individuals from published controls and publicly available population datasets. This variant is listed in the NHLBI Exome Sequencing Project dataset, where it was found in 11 of 6503 genotyped individuals (2 of 2203 African Americans and 9 of 4300 European Americans), indicating that it may be a rare benign variant. Another variant affecting the same residue, T3744P, was also seen in 1 of 6503 genotyped individuals. This variant, T3744N, has been listed in dpSNP, but has not been documented in 1000 genomes. It was observed in 1 of 200 published control individuals of African American descent (Sherman J et al., 2005).
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:
This variant is associated with the following publications: (PMID: 16253912, 23631430, 15178757, 31539150, 32164423, 23861362)
Comment:
ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler 2004 PMID:15178757, Lieve 2013 PMID:23631430). However, this variant is present in 0.1% (157/126452) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912705). This variant is present in ClinVar, with conflicting classifications of this variant (Variation ID:18057). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
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 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:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as a variant of unknown significance. This variant has been previously reported in two unrelated individuals with borderline prolonged QT intervals (Mohler P et at., 2004; due to alternative nomenclature, they report it as Thr1626Asn). One of the reported individuals had a daughter, also heterozygous for the variant, who died suddenly at age 19 with no prior cardiac symptoms. All other carriers of the variant in the two families were asymptomatic. This is a conservative amino acid change, resulting in the replacement of a threonine (polar) with an asparagine (polar). Threonine at this location is conserved across most mammalian species for which data is available with the exception of the mouse and x-tropicalis. In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” with a score of 0.951. In total, the variant has been seen in at least 12/6700 individuals from published controls and publicly available population datasets. This variant is listed in the NHLBI Exome Sequencing Project dataset, where it was found in 11 of 6503 genotyped individuals (2 of 2203 African Americans and 9 of 4300 European Americans), indicating that it may be a rare benign variant. Another variant affecting the same residue, T3744P, was also seen in 1 of 6503 genotyped individuals. This variant, T3744N, has been listed in dpSNP, but has not been documented in 1000 genomes. It was observed in 1 of 200 published control individuals of African American descent (Sherman J et al., 2005).
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 |
|---|---|---|---|---|
| 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 |
| The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
| Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. | Mohler PJ | Circulation | 2007 | PMID: 17242276 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ANK2 | - | - | - | - |
Text-mined citations for rs121912705 ...
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.