ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.3074G>C (p.Gly1025Ala) (rs773532854)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170692 SCV000223245 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing The G1025A variant of uncertain significance in the ANK2 gene has been previously reported in association with HCM (Lopes et al., 2015), although no clinical details or segregation data was provided. This variant has also been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This substitution occurs at a position that is conserved across species, and in silico analysis predicts G1025A is probably damaging to the protein structure/function. Nevertheless, G1025A is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. In addition, G1025A has been observed in 0.027% (18/66,552) of alleles from individuals of Non-Finnish European background. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV001094871 SCV000447167 uncertain significance Cardiac arrhythmia, ankyrin B-related 2018-01-12 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000621420 SCV000737961 uncertain significance Cardiovascular phenotype 2019-03-12 criteria provided, single submitter clinical testing The p.G1025A variant (also known as c.3074G>C), located in coding exon 27 of the ANK2 gene, results from a G to C substitution at nucleotide position 3074. The glycine at codon 1025 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001077 SCV001158207 uncertain significance not specified 2019-02-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000376133 SCV001212314 uncertain significance Long QT syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 1025 of the ANK2 protein (p.Gly1025Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs773532854, ExAC 0.03%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 190562). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001001077 SCV001372247 likely benign not specified 2020-06-15 criteria provided, single submitter clinical testing 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.

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