NM_001148.6(ANK2):c.3074G>C (p.Gly1025Ala) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jun 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001001077.2

Allele description [Variation Report for NM_001148.6(ANK2):c.3074G>C (p.Gly1025Ala)]

NM_001148.6(ANK2):c.3074G>C (p.Gly1025Ala)

Gene:
ANK2:ankyrin 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q26
Genomic location:
Preferred name:
NM_001148.6(ANK2):c.3074G>C (p.Gly1025Ala)
Other names:
p.G1025A:GGC>GCC
HGVS:
  • NC_000004.12:g.113330419G>C
  • NG_009006.2:g.517337G>C
  • NM_001127493.2:c.3047G>C
  • NM_001148.6:c.3074G>CMANE SELECT
  • NM_001354225.1:c.3086G>C
  • NM_001354228.1:c.3074G>C
  • NM_001354230.1:c.3152G>C
  • NM_001354231.1:c.3116G>C
  • NM_001354232.1:c.3110G>C
  • NM_001354235.1:c.3071G>C
  • NM_001354236.1:c.3071G>C
  • NM_001354237.1:c.3152G>C
  • NM_001354239.1:c.3044G>C
  • NM_001354240.1:c.3119G>C
  • NM_001354241.1:c.3119G>C
  • NM_001354242.1:c.3116G>C
  • NM_001354243.1:c.3011G>C
  • NM_001354244.1:c.3008G>C
  • NM_001354245.1:c.3011G>C
  • NM_001354246.1:c.3071G>C
  • NM_001354249.1:c.2987G>C
  • NM_001354252.1:c.3044G>C
  • NM_001354253.1:c.2948G>C
  • NM_001354254.1:c.3023G>C
  • NM_001354255.1:c.3011G>C
  • NM_001354256.1:c.3008G>C
  • NM_001354257.1:c.2912G>C
  • NM_001354258.1:c.3074G>C
  • NM_001354260.1:c.2888G>C
  • NM_001354261.1:c.3032G>C
  • NM_001354262.1:c.3011G>C
  • NM_001354264.1:c.2987G>C
  • NM_001354265.1:c.3071G>C
  • NM_001354266.1:c.2987G>C
  • NM_001354267.1:c.2987G>C
  • NM_001354268.1:c.2975G>C
  • NM_001354269.1:c.2861G>C
  • NM_001354270.1:c.2948G>C
  • NM_001354271.1:c.2888G>C
  • NM_001354272.1:c.3044G>C
  • NM_001354273.1:c.2873G>C
  • NM_001354274.1:c.2972G>C
  • NM_001354275.1:c.3011G>C
  • NM_001354276.1:c.2987G>C
  • NM_001354277.1:c.2789G>C
  • NM_001354278.1:c.701G>C
  • NM_001354279.1:c.737G>C
  • NM_001354280.1:c.701G>C
  • NM_001354281.1:c.701G>C
  • NM_001354282.1:c.737G>C
  • NM_020977.4:c.3074G>C
  • NP_001120965.1:p.Gly1016Ala
  • NP_001139.3:p.Gly1025Ala
  • NP_001341154.1:p.Gly1029Ala
  • NP_001341157.1:p.Gly1025Ala
  • NP_001341159.1:p.Gly1051Ala
  • NP_001341160.1:p.Gly1039Ala
  • NP_001341161.1:p.Gly1037Ala
  • NP_001341164.1:p.Gly1024Ala
  • NP_001341165.1:p.Gly1024Ala
  • NP_001341166.1:p.Gly1051Ala
  • NP_001341168.1:p.Gly1015Ala
  • NP_001341169.1:p.Gly1040Ala
  • NP_001341170.1:p.Gly1040Ala
  • NP_001341171.1:p.Gly1039Ala
  • NP_001341172.1:p.Gly1004Ala
  • NP_001341173.1:p.Gly1003Ala
  • NP_001341174.1:p.Gly1004Ala
  • NP_001341175.1:p.Gly1024Ala
  • NP_001341178.1:p.Gly996Ala
  • NP_001341181.1:p.Gly1015Ala
  • NP_001341182.1:p.Gly983Ala
  • NP_001341183.1:p.Gly1008Ala
  • NP_001341184.1:p.Gly1004Ala
  • NP_001341185.1:p.Gly1003Ala
  • NP_001341186.1:p.Gly971Ala
  • NP_001341187.1:p.Gly1025Ala
  • NP_001341189.1:p.Gly963Ala
  • NP_001341190.1:p.Gly1011Ala
  • NP_001341191.1:p.Gly1004Ala
  • NP_001341193.1:p.Gly996Ala
  • NP_001341194.1:p.Gly1024Ala
  • NP_001341195.1:p.Gly996Ala
  • NP_001341196.1:p.Gly996Ala
  • NP_001341197.1:p.Gly992Ala
  • NP_001341198.1:p.Gly954Ala
  • NP_001341199.1:p.Gly983Ala
  • NP_001341200.1:p.Gly963Ala
  • NP_001341201.1:p.Gly1015Ala
  • NP_001341202.1:p.Gly958Ala
  • NP_001341203.1:p.Gly991Ala
  • NP_001341204.1:p.Gly1004Ala
  • NP_001341205.1:p.Gly996Ala
  • NP_001341206.1:p.Gly930Ala
  • NP_001341207.1:p.Gly234Ala
  • NP_001341208.1:p.Gly246Ala
  • NP_001341209.1:p.Gly234Ala
  • NP_001341210.1:p.Gly234Ala
  • NP_001341211.1:p.Gly246Ala
  • NP_066187.2:p.Gly1025Ala
  • LRG_327t1:c.3074G>C
  • LRG_327:g.517337G>C
  • NC_000004.11:g.114251575G>C
  • NM_001148.4:c.3074G>C
Protein change:
G1003A
Links:
dbSNP: rs773532854
NCBI 1000 Genomes Browser:
rs773532854
Molecular consequence:
  • NM_001127493.2:c.3047G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001148.6:c.3074G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354225.1:c.3086G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354228.1:c.3074G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354230.1:c.3152G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354231.1:c.3116G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354232.1:c.3110G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354235.1:c.3071G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354236.1:c.3071G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354237.1:c.3152G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354239.1:c.3044G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354240.1:c.3119G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354241.1:c.3119G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354242.1:c.3116G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354243.1:c.3011G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354244.1:c.3008G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354245.1:c.3011G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354246.1:c.3071G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354249.1:c.2987G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354252.1:c.3044G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354253.1:c.2948G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354254.1:c.3023G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354255.1:c.3011G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354256.1:c.3008G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354257.1:c.2912G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354258.1:c.3074G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354260.1:c.2888G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354261.1:c.3032G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354262.1:c.3011G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354264.1:c.2987G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354265.1:c.3071G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354266.1:c.2987G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354267.1:c.2987G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354268.1:c.2975G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354269.1:c.2861G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354270.1:c.2948G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354271.1:c.2888G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354272.1:c.3044G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354273.1:c.2873G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354274.1:c.2972G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354275.1:c.3011G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354276.1:c.2987G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354277.1:c.2789G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354278.1:c.701G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354279.1:c.737G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354280.1:c.701G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354281.1:c.701G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354282.1:c.737G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020977.4:c.3074G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001158207ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Feb 27, 2019)
germlineclinical testing

Citation Link,

SCV001372247Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Jun 15, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.

Lopes LR, Syrris P, Guttmann OP, O'Mahony C, Tang HC, Dalageorgou C, Jenkins S, Hubank M, Monserrat L, McKenna WJ, Plagnol V, Elliott PM.

Heart. 2015 Feb;101(4):294-301. doi: 10.1136/heartjnl-2014-306387. Epub 2014 Oct 28.

PubMed [citation]
PMID:
25351510
PMCID:
PMC4345808

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001158207.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.Gly1025Ala variant (rs773532854) has been reported once in the medical literature in a cohort of patients with hypertrophic cardiomyopathy (Lopes 2015). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall frequency of 0.04 percent in the European Non-Finnish population (identified on 46 out of 128,804 chromosomes) and has been reported to the ClinVar database (Variation ID: 190562). The glycine at position 1025 is highly conserved and computational analyses of the effects of the p.Gly1025Ala variant on protein structure and function is conflicting (SIFT: tolerated, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Gly1025Ala variant with certainty.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372247.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: ANK2 c.3074G>C (p.Gly1025Ala) results in a non-conservative amino acid change located in the ZU5 domain (IPR000906) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251024 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 36 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3074G>C has been reported in the literature in at least one individual affected with hypertrophic cardiomyopathy (Lopes_2015). This report, however, does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitter (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 26, 2021

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