ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2659G>A (p.Ala887Thr) (rs148972050)

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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 RCV000171870 SCV000050882 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000171870 SCV000227785 uncertain significance not provided 2015-01-09 criteria provided, single submitter clinical testing
GeneDx RCV000171870 SCV000235705 uncertain significance not provided 2016-05-24 criteria provided, single submitter clinical testing The Ala887Thr variant in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala887Thr results in a non-conservative amino acid substitution of a nonpolar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala887Thr is possibly damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Ala887Thr was observed in 2/8,598 alleles from individuals of European background. Nevertheless, no mutations in nearby codons have been reported in association with DCM. With the clinical and molecular information available at this time, we cannot definitively determine if Ala887Thr is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV000638635 SCV000760172 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2017-12-12 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183278 SCV000280042 uncertain significance not specified 2015-04-08 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. The variant has not been reported in association with disease but has been seen at a low frequency in individuals who likely don't have cardiomyopathy. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. This is a non-conservative amino acid substitution of a nonpolar Alanine with a polar Threonine. The alanine at codon 887 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon or nearby codons (GeneDx report, google search, dbSNP clinical data, pubmed search, OMIM, ClinVar). In total the variant has been seen in 2 of 6503 individuals from publicly available population datasets. The variant was reported online in 2 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of December 31st, 2012). The phenotype of those 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. Note that other variants with strong evidence for pathogenicity have been seen at a similar frequency in this dataset so this observation is not necessarily incompatible with pathogenicity. The variant is listed in dbSNP (rs148972050) with reference only to the NHLBI ESP data (as of December 31st, 2012). The variant is listed in 1000 genomes, but only in reference to the dbSNP entry (as of December 31st, 2012).

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