NM_001148.6(ANK2):c.11231C>A (p.Thr3744Asn) AND Cardiac arrhythmia, ankyrin-B-related

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 30, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000019674.41

Allele description [Variation Report for NM_001148.6(ANK2):c.11231C>A (p.Thr3744Asn)]

NM_001148.6(ANK2):c.11231C>A (p.Thr3744Asn)

Gene:

ANK2:ankyrin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q26

Genomic location:

Preferred name:

NM_001148.6(ANK2):c.11231C>A (p.Thr3744Asn)

Other names:

p.T3744N:ACT>AAT

HGVS:

NC_000004.12:g.113367764C>A
NG_009006.2:g.554682C>A
NM_001127493.3:c.4949C>A
NM_001148.6:c.11231C>AMANE SELECT
NM_001354225.2:c.4988C>A
NM_001354228.2:c.4877C>A
NM_001354230.2:c.4955C>A
NM_001354231.2:c.5018C>A
NM_001354232.2:c.5012C>A
NM_001354235.2:c.4973C>A
NM_001354236.2:c.4874C>A
NM_001354237.2:c.5054C>A
NM_001354239.2:c.4946C>A
NM_001354240.2:c.5021C>A
NM_001354241.2:c.5021C>A
NM_001354242.2:c.5018C>A
NM_001354243.2:c.4913C>A
NM_001354244.2:c.4910C>A
NM_001354245.2:c.4814C>A
NM_001354246.2:c.4973C>A
NM_001354249.2:c.4790C>A
NM_001354252.2:c.4946C>A
NM_001354253.2:c.4751C>A
NM_001354254.2:c.4925C>A
NM_001354255.2:c.4913C>A
NM_001354256.2:c.4910C>A
NM_001354257.2:c.4715C>A
NM_001354258.2:c.4877C>A
NM_001354260.2:c.4691C>A
NM_001354261.2:c.4835C>A
NM_001354262.2:c.4814C>A
NM_001354264.2:c.4811C>A
NM_001354265.2:c.4973C>A
NM_001354266.2:c.4790C>A
NM_001354267.2:c.4790C>A
NM_001354268.2:c.4778C>A
NM_001354269.3:c.4763C>A
NM_001354270.2:c.4751C>A
NM_001354271.2:c.4691C>A
NM_001354272.2:c.4847C>A
NM_001354273.2:c.4676C>A
NM_001354274.2:c.4742C>A
NM_001354275.2:c.4814C>A
NM_001354276.2:c.4790C>A
NM_001354277.2:c.4592C>A
NM_001354278.2:c.2504C>A
NM_001354279.2:c.2540C>A
NM_001354280.2:c.2525C>A
NM_001354281.2:c.2504C>A
NM_001354282.2:c.2540C>A
NM_001386142.1:c.10997C>A
NM_001386143.1:c.4913C>A
NM_001386144.1:c.5021C>A
NM_001386146.1:c.4757C>A
NM_001386147.1:c.4802C>A
NM_001386148.2:c.4961C>A
NM_001386149.1:c.4757C>A
NM_001386150.1:c.4757C>A
NM_001386151.1:c.4691C>A
NM_001386152.1:c.5033C>A
NM_001386153.1:c.4757C>A
NM_001386154.1:c.4742C>A
NM_001386156.1:c.4715C>A
NM_001386157.1:c.4592C>A
NM_001386158.1:c.4493C>A
NM_001386160.1:c.4820C>A
NM_001386161.1:c.4910C>A
NM_001386162.1:c.4790C>A
NM_001386166.1:c.7631C>A
NM_001386167.1:c.1376C>A
NM_001386174.1:c.11372C>A
NM_001386175.1:c.11348C>A
NM_001386186.2:c.4961C>A
NM_001386187.2:c.4841C>A
NM_020977.5:c.4976C>A
NP_001120965.1:p.Thr1650Asn
NP_001139.3:p.Thr3744Asn
NP_001341154.1:p.Thr1663Asn
NP_001341157.1:p.Thr1626Asn
NP_001341159.1:p.Thr1652Asn
NP_001341160.1:p.Thr1673Asn
NP_001341161.1:p.Thr1671Asn
NP_001341164.1:p.Thr1658Asn
NP_001341165.1:p.Thr1625Asn
NP_001341166.1:p.Thr1685Asn
NP_001341168.1:p.Thr1649Asn
NP_001341169.1:p.Thr1674Asn
NP_001341170.1:p.Thr1674Asn
NP_001341171.1:p.Thr1673Asn
NP_001341172.1:p.Thr1638Asn
NP_001341173.1:p.Thr1637Asn
NP_001341174.1:p.Thr1605Asn
NP_001341175.1:p.Thr1658Asn
NP_001341178.1:p.Thr1597Asn
NP_001341181.1:p.Thr1649Asn
NP_001341182.1:p.Thr1584Asn
NP_001341183.1:p.Thr1642Asn
NP_001341184.1:p.Thr1638Asn
NP_001341185.1:p.Thr1637Asn
NP_001341186.1:p.Thr1572Asn
NP_001341187.1:p.Thr1626Asn
NP_001341189.1:p.Thr1564Asn
NP_001341190.1:p.Thr1612Asn
NP_001341191.1:p.Thr1605Asn
NP_001341193.1:p.Thr1604Asn
NP_001341194.1:p.Thr1658Asn
NP_001341195.1:p.Thr1597Asn
NP_001341196.1:p.Thr1597Asn
NP_001341197.1:p.Thr1593Asn
NP_001341198.1:p.Thr1588Asn
NP_001341199.1:p.Thr1584Asn
NP_001341200.1:p.Thr1564Asn
NP_001341201.1:p.Thr1616Asn
NP_001341202.1:p.Thr1559Asn
NP_001341203.1:p.Thr1581Asn
NP_001341204.1:p.Thr1605Asn
NP_001341205.1:p.Thr1597Asn
NP_001341206.1:p.Thr1531Asn
NP_001341207.1:p.Thr835Asn
NP_001341208.1:p.Thr847Asn
NP_001341209.1:p.Thr842Asn
NP_001341210.1:p.Thr835Asn
NP_001341211.1:p.Thr847Asn
NP_001373071.1:p.Thr3666Asn
NP_001373072.1:p.Thr1638Asn
NP_001373073.1:p.Thr1674Asn
NP_001373075.1:p.Thr1586Asn
NP_001373076.1:p.Thr1601Asn
NP_001373077.1:p.Thr1654Asn
NP_001373078.1:p.Thr1586Asn
NP_001373079.1:p.Thr1586Asn
NP_001373080.1:p.Thr1564Asn
NP_001373081.1:p.Thr1678Asn
NP_001373082.1:p.Thr1586Asn
NP_001373083.1:p.Thr1581Asn
NP_001373085.1:p.Thr1572Asn
NP_001373086.1:p.Thr1531Asn
NP_001373087.1:p.Thr1498Asn
NP_001373089.1:p.Thr1607Asn
NP_001373090.1:p.Thr1637Asn
NP_001373091.1:p.Thr1597Asn
NP_001373095.1:p.Thr2544Asn
NP_001373096.1:p.Thr459Asn
NP_001373103.1:p.Thr3791Asn
NP_001373104.1:p.Thr3783Asn
NP_001373115.1:p.Thr1654Asn
NP_001373116.1:p.Thr1614Asn
NP_066187.2:p.Thr1659Asn
LRG_327t1:c.11231C>A
LRG_327:g.554682C>A
NC_000004.11:g.114288920C>A
NM_001148.4:c.11231C>A
NM_001148.5:c.11231C>A
Q01484:p.Thr3744Asn

Protein change:

T1498N; THR1626ASN

Links:

UniProtKB: Q01484#VAR_022936; OMIM: 106410.0002; dbSNP: rs121912705

NCBI 1000 Genomes Browser:

rs121912705

Molecular consequence:

NM_001127493.3:c.4949C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001148.6:c.11231C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354225.2:c.4988C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354228.2:c.4877C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354230.2:c.4955C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354231.2:c.5018C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354232.2:c.5012C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354235.2:c.4973C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354236.2:c.4874C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354237.2:c.5054C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354239.2:c.4946C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354240.2:c.5021C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354241.2:c.5021C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354242.2:c.5018C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354243.2:c.4913C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354244.2:c.4910C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354245.2:c.4814C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354246.2:c.4973C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354249.2:c.4790C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354252.2:c.4946C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354253.2:c.4751C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354254.2:c.4925C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354255.2:c.4913C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354256.2:c.4910C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354257.2:c.4715C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354258.2:c.4877C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354260.2:c.4691C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354261.2:c.4835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354262.2:c.4814C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354264.2:c.4811C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354265.2:c.4973C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354266.2:c.4790C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354267.2:c.4790C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354268.2:c.4778C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354269.3:c.4763C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354270.2:c.4751C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354271.2:c.4691C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354272.2:c.4847C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354273.2:c.4676C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354274.2:c.4742C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354275.2:c.4814C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354276.2:c.4790C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354277.2:c.4592C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354278.2:c.2504C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354279.2:c.2540C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354280.2:c.2525C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354281.2:c.2504C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354282.2:c.2540C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386142.1:c.10997C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386143.1:c.4913C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386144.1:c.5021C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386146.1:c.4757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386147.1:c.4802C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386148.2:c.4961C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386149.1:c.4757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386150.1:c.4757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386151.1:c.4691C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386152.1:c.5033C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386153.1:c.4757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386154.1:c.4742C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386156.1:c.4715C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386157.1:c.4592C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386158.1:c.4493C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386160.1:c.4820C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386161.1:c.4910C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386162.1:c.4790C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386166.1:c.7631C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386167.1:c.1376C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386174.1:c.11372C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386175.1:c.11348C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386186.2:c.4961C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386187.2:c.4841C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020977.5:c.4976C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiac arrhythmia, ankyrin-B-related
Synonyms:: ANKYRIN-B SYNDROME
Identifiers:: MONDO: MONDO:0010958; MedGen: C1970119; Orphanet: 101016; Orphanet: 768; OMIM: 600919

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039972	OMIM	no assertion criteria provided	Pathogenic (Jun 15, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001304614	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23861362, 23631430, 15178757, 17242276, 16253912, 19862833 Citation Link,
SCV003920126	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000039972

OMIM

no assertion criteria provided

Pathogenic
(Jun 15, 2004)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001304614

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV003920126

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 30, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.

Lieve KV, Williams L, Daly A, Richard G, Bale S, Macaya D, Chung WK.

Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. doi: 10.1089/gtmb.2012.0118. Epub 2013 Apr 30.

PubMed [citation]

PMID:: 23631430

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000039972.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001304614.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920126.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 29, 2024

ClinVar

Relating variation to medicine