Submissions for variant NM_000256.3(MYBPC3):c.2942A>C (p.Gln981Pro)

dbSNP: rs730880582

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158201	SCV000208136	likely pathogenic	not provided	2013-08-12	criteria provided, single submitter	clinical testing	This variant is denoted p.Gln981Pro (CAG>CCG): c.2942 A>C in exon 28 of the MYBPC3 gene (NM_000256.3). The Gln981Pro variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gln981Pro results in a non-conservative amino acid substitution of a polar Glutamine to a non-polar Proline at a position that is conserved across species. In silico analysis predicts Gln981Pro is damaging to the protein structure/function. A mutation in nearby residue (Pro976Arg) has been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Gln981Pro variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Gln981Pro is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001191622	SCV001359508	uncertain significance	Cardiomyopathy	2019-12-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 981 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223801	SCV000280253	uncertain significance	not specified	2014-04-04	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. MYBPC3 p.Gln981Pro Based on the lack of case data we consider this variant a variant of uncertain significance. This variant is novel. p.Gln981Pro results in a non-conservative amino acid substitution of a polar Glutamine to a non-polar Proline in exon 28 of the MYBPC3 gene. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The Glutamine at codon 981 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Pro976Arg). In total the variant has not been seen in ~6,500 laboratory controls and published controls and individuals from publicly available population datasets. There is no variation at codon 981 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/30/13). There is no variation at codon 981 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 5th, 2014).