ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.11594A>G (p.Asp3865Gly) (rs140606121)

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Total submissions: 5
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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 RCV000170744 SCV000050643 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000170744 SCV000223297 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing The D3865G variant of uncertain significance has been identified in the ANK2 gene. This variant has been previously reported in one individual referred for LQTS genetic testing at GeneDx (Lieve et al., 2013). The D3865G variant has also been identified independently of other cardiogenetic variants in one other individual referred for arrhythmia genetic testing at GeneDx. However, thus far, segregation data is absent for these individual due to the lack of clinical information provided and insufficient participation by informative family members. The D3865G variant was not observed with any significant frequency in either the NHLBI Exome Sequencing Project or the Exome Aggregation Consortium. The D3865G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved, and G3865 is tolerated in at least two species. Furthermore, the majority of in silico tools predict this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000530694 SCV000627620 uncertain significance Long QT syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 3865 of the ANK2 protein (p.Asp3865Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs140606121, ExAC 0.008%). This variant has been reported in the literature in an individual that has been referred to long QT genetic testing (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 190610). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618820 SCV000737550 uncertain significance Cardiovascular phenotype 2019-09-30 criteria provided, single submitter clinical testing The p.D3865G variant (also known as c.11594A>G), located in coding exon 43 of the ANK2 gene, results from an A to G substitution at nucleotide position 11594. The aspartic acid at codon 3865 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in a cohort referred for long QT syndrome genetic testing, and has been reported as a secondary cardiac variant in an exome cohort; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and glycine is the reference amino acid in other 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000170744 SCV001154265 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing

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