ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1003C>T (p.Arg335Cys) (rs730880630)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158326 SCV000208261 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing The R335C variant of uncertain significance in the MYBPC3 gene has been previously reported in association with HCM, although no clinical information or segregation data was provided (Cecconi et al., 2016). This variant has also been reported in an infant with sudden cardiac death in his sleep at one year of age who was found to have an interventricular septum thickness of 7 mm on autopsy (Bagnall et al., 2016). Furthermore, R335C has been identified independently of additional cardiogenetic variants in two other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members.The R335C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, R335C 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. This substitution also occurs at a position where only amino acids with similar properties to arginine are tolerated across species. In silico analysis predicts R335C is probably damaging to the protein structure/function. Nevertheless, R335C is classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000254434.1; Landrum et al., 2016). Moreover, this variant lacks observation in a significant number of affected individuals, informative segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000200384 SCV000254434 uncertain significance Hypertrophic cardiomyopathy 2015-06-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 335 of the MYBPC3 protein (p.Arg335Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant has not been published in the literature and is present in population databases (no rsID, <0.01%). ClinVar contains an entry for this variant (RCV000158326). 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. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000279000 SCV000372371 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334105 SCV000372372 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000200384 SCV000372373 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620005 SCV000737376 uncertain significance Cardiovascular phenotype 2016-11-01 criteria provided, single submitter clinical testing Insufficient evidence

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