ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.130C>G (p.Leu44Val) (rs145272651)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250584 SCV000320044 uncertain significance Cardiovascular phenotype 2020-10-05 criteria provided, single submitter clinical testing The p.L44V variant (also known as c.130C>G), located in coding exon 2 of the ANK2 gene, results from a C to G substitution at nucleotide position 130. The leucine at codon 44 is replaced by valine, an amino acid with highly similar properties. This variant was detected in a cohort referred for long QT syndrome genetic testing; however, clinical details were not provided (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17(7):553-61). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
GeneDx RCV000436774 SCV000512026 uncertain significance not specified 2016-11-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANK2 gene. Although the L44V variant has not been published as a pathogenic variant or reported as a benign variant to our knowledge, it has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000320044.1; Landrum et al., 2016). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species and where Valine is the wild type in the lizard. Furthermore, the L44V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The NHLBI Exome Sequencing Project and 1000 Genomes Project reports L44V was observed at low frequency in individuals of African American ancestry (4/4406 alleles, 0.1%) and African ancestry (1/1322 alleles, ~0.2%), respectively.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000865942 SCV001006972 likely benign not provided 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV001433540 SCV001636331 likely benign Long QT syndrome 2020-11-11 criteria provided, single submitter clinical testing

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