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

gnomAD frequency: 0.00010  dbSNP: rs150226540

Total submissions: 7

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	RCV000170670	SCV000223223	benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000382392	SCV000627690	benign	Long QT syndrome	2025-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618444	SCV000738214	benign	Cardiovascular phenotype	2017-10-31	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
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.
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.