ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3614G>A (p.Arg1205Gln) (rs730880596)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158247 SCV000208182 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The R1205Q variant has been reported as a variant of uncertain significance in the Framingham and Jackson Heart Study cohort because it was seen in one individual without hypertrophy (Bick et al., 2012). This variant was subsequently reported in an individual with reported HCM, however, it is unclear whether this individual harbored additional potentially pathogenic variants (Walsh et al., 2017). It is also reported as a variant of uncertain significance in ClinVar by two different clinical laboratories (ClinVar SCV000219069.2; SCV000537832.1; Landrum et al., 2016), and has been observed in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. However, no informative segregation data is available for these individuals. Furthermore, although missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in association with cardiomyopathy, the clinical significance of these variants is currently unknown (Stenson et al., 2014).Nevertheless, the R1205Q variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016). R1205Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Lastly, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000168378 SCV000219069 uncertain significance Hypertrophic cardiomyopathy 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1205 of the MYBPC3 protein (p.Arg1205Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181014). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Claritas Genomics RCV000449593 SCV000537832 uncertain significance Peripheral neuropathy 2016-08-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618734 SCV000737301 uncertain significance Cardiovascular phenotype 2017-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000777734 SCV000913692 uncertain significance Cardiomyopathy 2018-08-28 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-like domain C10 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/276174 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Blueprint Genetics RCV000158247 SCV000927289 uncertain significance not provided 2017-06-10 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.