Submissions for variant NM_001148.6(ANK2):c.3373G>C (p.Asp1125His)

gnomAD frequency: 0.00002  dbSNP: rs1043468981

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756992	SCV000885006	uncertain significance	not provided	2018-05-06	criteria provided, single submitter	clinical testing	The p.Asp1125His variant (rs1043468981) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.001percent (identified on 3 out of 277,142 chromosomes). The aspartic acid at position 1125 is highly conserved up to tetraodon considering 12 species (Alamut v2.11) and computational analyses of the p.Asp1125His variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Asp1125His variant with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227426	SCV001399785	uncertain significance	Long QT syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1125 of the ANK2 protein (p.Asp1125His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 618528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANK2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002458357	SCV002616821	uncertain significance	Cardiovascular phenotype	2020-12-04	criteria provided, single submitter	clinical testing	The p.D1125H variant (also known as c.3373G>C), located in coding exon 29 of the ANK2 gene, results from a G to C substitution at nucleotide position 3373. The aspartic acid at codon 1125 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000756992	SCV004026304	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing