ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.962G>A (p.Arg321Gln) (rs150226540)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000170670 SCV000050743 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000185493 SCV000223223 likely benign not specified 2018-01-23 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV001094854 SCV000447147 likely benign Cardiac arrhythmia, ankyrin B-related 2018-01-13 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000382392 SCV000627690 benign Long QT syndrome 2020-11-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618444 SCV000738214 benign Cardiovascular phenotype 2017-10-31 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000170670 SCV000885003 likely benign not provided 2017-12-22 criteria provided, single submitter clinical testing The p.Arg321Gln variant (rs150226540) has been previously observed in three individuals included in a large cohort of cardiomyopathy patients, where it was classified as likely not pathogenic based on population frequency (Ng 2013). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 1.4 percent in the Ashkenazi Jewish population (identified on 142 out of 10,126 chromosomes, including 1 homozygote), and is listed in the ClinVar database (Variation ID: 190540). The arginine at position 321 is moderately conserved considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Arg321Gln variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Given the current evidence, this variant is considered to be likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000170670 SCV001154228 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000185493 SCV001554566 benign not specified 2021-03-25 criteria provided, single submitter clinical testing Variant summary: ANK2 c.962G>A (p.Arg321Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 250854 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 111.82 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.962G>A in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.

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