ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.556C>T (p.Leu186Phe) (rs371930065)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620752 SCV000740154 uncertain significance Cardiovascular phenotype 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769751 SCV000901173 uncertain significance Cardiomyopathy 2016-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000487140 SCV000567802 uncertain significance not provided 2017-03-13 criteria provided, single submitter clinical testing The L186F variant of uncertain significance in the ACTN2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L186F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position that is conserved in mammals, phenylalanine is is tolerated at this position in several non-mammalian species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000229218 SCV000285875 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 186 of the ACTN2 protein (p.Leu186Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs371930065, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 238302). 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: "Benign"; Align-GVGD: "Class C15"). 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000487140 SCV000925025 uncertain significance not provided 2016-03-01 no assertion criteria provided provider interpretation

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