ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.6272A>G (p.Asn2091Ser) (rs201090446)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000357942 SCV000254657 likely benign not provided 2019-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000357942 SCV000329185 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing The N2091S variant (reported as N2174S by the research laboratory due to alternative transcript) was reported in a 20 year-old Asian male with sudden unexplained death (SUD) diagnosed by autopsy with myocyte hypertrophy (Bagnall et al., 2014). The N2091S variant was also reported in an abstract in three family members with LQTS-phenotype (Laish-Farkash et al., 2009). The proband, who also carried a CACNA1C G490R pathogenic variant, presented with incessant ventricular bidirectional tachycardia, recurrent syncope, intermittent prolonged QT interval and dysmorphic features (Laish-Farkash et al., 2009). Nevertheless, the 1000 Genomes Project reports N2091S was observed in 1/978 alleles (0.1%) from individuals of South Asian ancestry, indicating it may be a rare benign variant in these populations. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CACNA1C-related disorders (Stenson et al., 2014). Given the available evidence, we consider N2091S as a variant of uncertain significance.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000519629 SCV000616620 uncertain significance Timothy syndrome 2017-04-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617693 SCV000737727 uncertain significance Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Ambry Genetics RCV000717339 SCV000848189 uncertain significance History of neurodevelopmental disorder 2018-11-08 criteria provided, single submitter clinical testing Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000357942 SCV001148544 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678781 SCV000804961 uncertain significance Cardiac arrhythmia 2016-08-18 no assertion criteria provided clinical testing

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