ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1720C>T (p.Arg574Trp) (rs61897383)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158109 SCV000208044 likely pathogenic not provided 2014-08-22 criteria provided, single submitter clinical testing p.Arg574Trp (CGG>TGG): c.1720 C>T in exon 18 of the MYBPC3 gene (NM_000256.3)A R574W variant that is likely pathogenic was identified in the MYBPC3 gene. It has not been published as a mutation or a benign polymorphism to our knowledge. The R574W variant was not observed in approximately 6,300 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 addition, the R574W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, one missense mutation in a nearby residue (C566R) has been reported in association with HCM, supporting the functional importance of this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with HCM, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (DCM) (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV000556907 SCV000623531 uncertain significance Hypertrophic cardiomyopathy 2017-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 574 of the MYBPC3 protein (p.Arg574Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs61897383, ExAC 0.02%) but has not been reported in the literature in individuals with a MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 180947). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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