ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3005G>A (p.Arg1002Gln) (rs727504235)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000208257 SCV000264038 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000766363 SCV000208142 uncertain significance not provided 2017-11-13 criteria provided, single submitter clinical testing This variant is denoted p.Arg1002Gln (CGG>CAG): c.3005 G>A in exon 29 of the MYBPC3 gene (NM_000256.3). A variant of uncertain significance has been identified in the MYBPC3 gene. The R1002Q variant has been reported in association with HCM (Niimura et al., 2002; Ho et al., 2009; Coppini et al., 2014); however, segregation information and functional studies were not included. Additionally, this variant inconsistently classified in ClinVar as a variant of uncertain significance (SCV000203853.3; Landum et al., 2016) and as a likely pathogenic variant (SCV000264038.1). Nevertheless, the R1002Q variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000688819 SCV000816443 uncertain significance Hypertrophic cardiomyopathy 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1002 of the MYBPC3 protein (p.Arg1002Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs727504235, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy and in an individual with dilated cardiomyopathy (PMID: 11815426, 28790153, 27532257). This variant has also been reported in an infant with sudden death (PMID: 28807990). ClinVar contains an entry for this variant (Variation ID: 177622). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154201 SCV000203853 uncertain significance not specified 2014-12-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg1002Gln var iant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 20 09 and LVOD unpublished data). This variant was also identified by our laborator y in 1 individual with DCM and in 1 individual with giant right atrium and arrhy thmia (LMM unpublished data). In addition, this variant was identified in 4/6209 2 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolution arily distant species and the change to glutamine (Gln) is present in several bi rds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significanc e of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign.

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