Submissions for variant NM_000256.3(MYBPC3):c.340A>G (p.Thr114Ala)

dbSNP: rs730880612

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766308	SCV000208211	uncertain significance	not provided	2013-08-14	criteria provided, single submitter	clinical testing	p.Thr114Ala (ACT>GCT): c.340 A>G in exon 3 of the MYBPC3 gene (NM_000256.3)The Thr114Ala variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Thr114Ala results in a non-conservative amino acid substitution of a neutral, polar Threonine with a non-polar Alanine, the Thr114Ala position is not conserved across species. In silico analysis predicts Thr114Ala is benign to the protein structure/function. No mutations in nearby residues have been reported in association with HCM, indicating this region of the protein may be tolerant of change. However, the Thr114Ala variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if Thr114Ala 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).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158276	SCV000280262	uncertain significance	not specified	2014-01-03	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. p.Thr114Ala in the MYBPC3 gene. Based on the data reviewed below we consider this variant a variant of uncertain significance. This variant is novel. Thr114Ala results in a non-conservative amino acid substitution of a neutral, polar threonine with a non-polar Alanine. The Thr114Ala positive is not conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be benign. Mutation taster predicts this variant to be a polymorphism. The Threonine at codon 114 is not conserved across species, nor are neighboring amino acids. No other variants have been reported in association with disease at this codon nor at nearby codons. In total the variant has not been seen in individuals from publicly available population datasets. There is no variation at codon 114 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/5/13). Note that this dataset does not match the patient's ancestry (China). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/5/13 ). GeneDx did not include internal control data