ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.566T>A (p.Val189Asp) (rs397516060)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766312 SCV000208230 uncertain significance not provided 2012-12-07 criteria provided, single submitter clinical testing p.Val189Asp (GTC>GAC): c.566 T>A in exon 5 of the MYBPC3 gene (NM_000256.3). The Val189Asp variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val189Asp results in a non-conservative amino acid substitution of a non-polar Valine with a negatively charged Aspartic acid at a position that is conserved across species. In silico analysis predicts Val189Asp is probably damaging to the protein structure/function. Mutations in nearby residues (Pro186Leu, Lys202Gln) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Val189Asp was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, two other amino acid substitutions at this codon (Val189Ile, Val189Leu) have been reported as likely benign or polymorphisms indicating this residue may be tolerant of change (Lakdawala N et al., 2012; Girolami F et al., 2006). With the clinical and molecular information available at this time, we cannot definitively determine if Val189Asp is a disease-causing mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Ambry Genetics RCV000622174 SCV000740212 uncertain significance Cardiovascular phenotype 2017-08-30 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 RCV000769359 SCV000900747 uncertain significance Cardiomyopathy 2015-10-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035649 SCV000059300 uncertain significance not specified 2008-03-01 no assertion criteria provided clinical testing

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