ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1691C>T (p.Thr564Met) (rs876661341)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244263 SCV000317770 uncertain significance Cardiovascular phenotype 2012-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223850 SCV000280039 uncertain significance not specified 2015-09-23 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This is a novel variant and has not been reported previously in an affected individual. This is a non-conservative amino acid change from a polar threonine to a nonpolar methionine. It is at an amino acid residue that is conserved across 39 vertebrate species sequenced, as are the flanking amino acids. No variation at nearby residues has been associated with disease in HGMD or ClinVar (HGMD professional version checked January 17, 2014). It is predicted to be “probably damaging” and “deleterious” by PolyPhen and SIFT in silico analyses, respectively. In total the variant has not been seen in ~60,000 individuals from publicly available population datasets. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals, The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 4/8/2015. Variation at this codon also has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian).

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