ClinVar Genomic variation as it relates to human health
NM_001148.6(ANK2):c.11354A>G (p.Gln3785Arg)
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(6); 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.11354A>G (p.Gln3785Arg)
Variation ID: 190580 Accession: VCV000190580.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q26 4: 113369549 (GRCh38) [ NCBI UCSC ] 4: 114290705 (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 9, 2016 May 12, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001148.6:c.11354A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001139.3:p.Gln3785Arg missense NM_001127493.3:c.5072A>G NP_001120965.1:p.Gln1691Arg missense NM_001354225.2:c.5111A>G NP_001341154.1:p.Gln1704Arg missense NM_001354228.2:c.5000A>G NP_001341157.1:p.Gln1667Arg missense NM_001354230.2:c.5078A>G NP_001341159.1:p.Gln1693Arg missense NM_001354231.2:c.5141A>G NP_001341160.1:p.Gln1714Arg missense NM_001354232.2:c.5135A>G NP_001341161.1:p.Gln1712Arg missense NM_001354235.2:c.5096A>G NP_001341164.1:p.Gln1699Arg missense NM_001354236.2:c.4997A>G NP_001341165.1:p.Gln1666Arg missense NM_001354237.2:c.5177A>G NP_001341166.1:p.Gln1726Arg missense NM_001354239.2:c.5069A>G NP_001341168.1:p.Gln1690Arg missense NM_001354240.2:c.5144A>G NP_001341169.1:p.Gln1715Arg missense NM_001354241.2:c.5144A>G NP_001341170.1:p.Gln1715Arg missense NM_001354242.2:c.5141A>G NP_001341171.1:p.Gln1714Arg missense NM_001354243.2:c.5036A>G NP_001341172.1:p.Gln1679Arg missense NM_001354244.2:c.5033A>G NP_001341173.1:p.Gln1678Arg missense NM_001354245.2:c.4937A>G NP_001341174.1:p.Gln1646Arg missense NM_001354246.2:c.5096A>G NP_001341175.1:p.Gln1699Arg missense NM_001354249.2:c.4913A>G NP_001341178.1:p.Gln1638Arg missense NM_001354252.2:c.5069A>G NP_001341181.1:p.Gln1690Arg missense NM_001354253.2:c.4874A>G NP_001341182.1:p.Gln1625Arg missense NM_001354254.2:c.5048A>G NP_001341183.1:p.Gln1683Arg missense NM_001354255.2:c.5036A>G NP_001341184.1:p.Gln1679Arg missense NM_001354256.2:c.5033A>G NP_001341185.1:p.Gln1678Arg missense NM_001354257.2:c.4838A>G NP_001341186.1:p.Gln1613Arg missense NM_001354258.2:c.5000A>G NP_001341187.1:p.Gln1667Arg missense NM_001354260.2:c.4814A>G NP_001341189.1:p.Gln1605Arg missense NM_001354261.2:c.4958A>G NP_001341190.1:p.Gln1653Arg missense NM_001354262.2:c.4937A>G NP_001341191.1:p.Gln1646Arg missense NM_001354264.2:c.4934A>G NP_001341193.1:p.Gln1645Arg missense NM_001354265.2:c.5096A>G NP_001341194.1:p.Gln1699Arg missense NM_001354266.2:c.4913A>G NP_001341195.1:p.Gln1638Arg missense NM_001354267.2:c.4913A>G NP_001341196.1:p.Gln1638Arg missense NM_001354268.2:c.4901A>G NP_001341197.1:p.Gln1634Arg missense NM_001354269.3:c.4886A>G NP_001341198.1:p.Gln1629Arg missense NM_001354270.2:c.4874A>G NP_001341199.1:p.Gln1625Arg missense NM_001354271.2:c.4814A>G NP_001341200.1:p.Gln1605Arg missense NM_001354272.2:c.4970A>G NP_001341201.1:p.Gln1657Arg missense NM_001354273.2:c.4799A>G NP_001341202.1:p.Gln1600Arg missense NM_001354274.2:c.4865A>G NP_001341203.1:p.Gln1622Arg missense NM_001354275.2:c.4937A>G NP_001341204.1:p.Gln1646Arg missense NM_001354276.2:c.4913A>G NP_001341205.1:p.Gln1638Arg missense NM_001354277.2:c.4715A>G NP_001341206.1:p.Gln1572Arg missense NM_001354278.2:c.2627A>G NP_001341207.1:p.Gln876Arg missense NM_001354279.2:c.2663A>G NP_001341208.1:p.Gln888Arg missense NM_001354280.2:c.2648A>G NP_001341209.1:p.Gln883Arg missense NM_001354281.2:c.2627A>G NP_001341210.1:p.Gln876Arg missense NM_001354282.2:c.2663A>G NP_001341211.1:p.Gln888Arg missense NM_001386142.1:c.11120A>G NP_001373071.1:p.Gln3707Arg missense NM_001386143.1:c.5036A>G NP_001373072.1:p.Gln1679Arg missense NM_001386144.1:c.5144A>G NP_001373073.1:p.Gln1715Arg missense NM_001386146.1:c.4880A>G NP_001373075.1:p.Gln1627Arg missense NM_001386147.1:c.4925A>G NP_001373076.1:p.Gln1642Arg missense NM_001386148.2:c.5084A>G NP_001373077.1:p.Gln1695Arg missense NM_001386149.1:c.4880A>G NP_001373078.1:p.Gln1627Arg missense NM_001386150.1:c.4880A>G NP_001373079.1:p.Gln1627Arg missense NM_001386151.1:c.4814A>G NP_001373080.1:p.Gln1605Arg missense NM_001386152.1:c.5156A>G NP_001373081.1:p.Gln1719Arg missense NM_001386153.1:c.4880A>G NP_001373082.1:p.Gln1627Arg missense NM_001386154.1:c.4865A>G NP_001373083.1:p.Gln1622Arg missense NM_001386156.1:c.4838A>G NP_001373085.1:p.Gln1613Arg missense NM_001386157.1:c.4715A>G NP_001373086.1:p.Gln1572Arg missense NM_001386158.1:c.4616A>G NP_001373087.1:p.Gln1539Arg missense NM_001386160.1:c.4943A>G NP_001373089.1:p.Gln1648Arg missense NM_001386161.1:c.5033A>G NP_001373090.1:p.Gln1678Arg missense NM_001386162.1:c.4913A>G NP_001373091.1:p.Gln1638Arg missense NM_001386166.1:c.7754A>G NP_001373095.1:p.Gln2585Arg missense NM_001386167.1:c.1499A>G NP_001373096.1:p.Gln500Arg missense NM_001386174.1:c.11495A>G NP_001373103.1:p.Gln3832Arg missense NM_001386175.1:c.11471A>G NP_001373104.1:p.Gln3824Arg missense NM_001386186.2:c.5084A>G NP_001373115.1:p.Gln1695Arg missense NM_001386187.2:c.4964A>G NP_001373116.1:p.Gln1655Arg missense NM_020977.5:c.5099A>G NP_066187.2:p.Gln1700Arg missense NC_000004.12:g.113369549A>G NC_000004.11:g.114290705A>G NG_009006.2:g.556467A>G LRG_327:g.556467A>G LRG_327t1:c.11354A>G - Protein change
- Q1691R, Q3785R, Q1638R, Q1653R, Q1678R, Q1690R, Q1693R, Q1700R, Q1715R, Q1572R, Q1600R, Q1605R, Q1613R, Q1622R, Q1625R, Q1645R, Q1683R, Q1704R, Q1712R, Q1726R, Q1629R, Q1634R, Q1657R, Q1666R, Q1667R, Q1679R, Q876R, Q883R, Q1646R, Q1699R, Q1714R, Q888R, Q1539R, Q1627R, Q1642R, Q1648R, Q1655R, Q1695R, Q1719R, Q2585R, Q3707R, Q3824R, Q3832R, Q500R
- Other names
- p.Q3785R:CAG>CGG
- p.Gln3785Arg
- Canonical SPDI
- NC_000004.12:113369548: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
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 |
2586 | 3157 |
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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Likely benign (1) |
criteria provided, single submitter
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Nov 24, 2021 | RCV000243482.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV000529321.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 1, 2023 | RCV000786100.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 7, 2021 | RCV001144040.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 20, 2021 | RCV001804900.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 1, 2022 | RCV003422063.4 |
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
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia, ankyrin-B-related
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001304615.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Dec 20, 2021)
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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: SCV002051276.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: ANK2 c.11354A>G (p.Gln3785Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: ANK2 c.11354A>G (p.Gln3785Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251000 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11354A>G has been reported in the literature in an individual with a QTc interval value of 464ms (Ghouse_2015). This report does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=4), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Nov 24, 2021)
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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: SCV000318623.7
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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Likely benign
(Feb 28, 2022)
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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: SCV000223266.13
First in ClinVar: May 23, 2015 Last updated: Mar 04, 2023 |
Comment:
See Variant Classification Assertion Criteria.
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Uncertain significance
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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ANK2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116516.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ANK2 c.11354A>G variant is predicted to result in the amino acid substitution p.Gln3785Arg. This variant has been reported in an individual with an apparently … (more)
The ANK2 c.11354A>G variant is predicted to result in the amino acid substitution p.Gln3785Arg. This variant has been reported in an individual with an apparently normal QTc interval (Table S3, Ghouse et al. 2015. PubMed ID: 26159999). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-114290705-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jan 24, 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: SCV000627617.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 3785 of the ANK2 protein (p.Gln3785Arg). … (more)
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 3785 of the ANK2 protein (p.Gln3785Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with a normal QTc interval (PMID: 26159999). ClinVar contains an entry for this variant (Variation ID: 190580). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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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Uncertain significance
(May 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia, ankyrin-B-related
Affected status: yes
Allele origin:
germline
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Clinical Genomics Program, Stanford Medicine
Accession: SCV004801300.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The p.Gln3785Arg variant in the ANK2 gene has been previously reported in 1 individual with a QTc interval of 464ms (Ghouse et al., 2015). This … (more)
The p.Gln3785Arg variant in the ANK2 gene has been previously reported in 1 individual with a QTc interval of 464ms (Ghouse et al., 2015). This variant has also been identified in 6/19,922 East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Gln3785Arg variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gln3785Arg variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: none] (less)
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Uncertain significance
(Feb 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004148765.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 15, 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: SCV000924741.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
ANK2, Exon 43, c.11354A>G (p.Gln3785Arg), heterozygous, Uncertain Significance Given the lack of case data and the frequency in gnomAD, we consider this variant a variant … (more)
ANK2, Exon 43, c.11354A>G (p.Gln3785Arg), heterozygous, Uncertain Significance Given the lack of case data and the frequency in gnomAD, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report this variant has not been reported in association with disease. This variant is listed in ClinVar and is also classified as a VUS by Ambry and GeneDx. Per the information in ClinVar from GeneDx, this variant has been in seen in conjunction with other pathogenic variants in individuals with an unspecified arrhythmia or Long QT syndrome. GeneDx has also seen it in the homozygous state in one individual with Long QT syndrome or another unspecified arrhythmia. No segregation data. The variant was reported online in 8 of 138,365 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in East Asians, Africans, and Latinos with the highest MAF in East Asians (6 of 9421 individuals (MAF=0.03184%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. (less)
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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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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 |
Text-mined citations for rs150808807 ...
HelpRecord last updated May 12, 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.