ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3787C>T (p.Arg1263Trp) (rs370338674)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000724227 SCV000208200 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing The R1263W variant of uncertain significance in the MYBPC3 gene has not been published in association with cardiomyopathy to our knowledge. This variant has been identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. Thus far, segregation data is absent due to the lack of participation by informative family members. The R1263W variant is also observed in 18/23,968 (0.075%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). In addition, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, R1263W 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.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724227 SCV000229589 uncertain significance not provided 2015-08-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000158265 SCV000271996 uncertain significance not specified 2015-04-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg1263Trp va riant in MYBPC3 has not been previously reported in individuals with cardiomyopa thy, but has been identified in 3/9594 African chromosomes by the Exome Aggregat ion Consortium (ExAC,; dbSNP rs370338674). Argini ne (Arg) at position 1263 is not conserved evolution and the change to tryptopha n (Trp) was predicted to be benign using a computational tool clinically validat ed by our laboratory. This tool's benign prediction is estimated to be correct 8 9% of the time (Jordan 2011). In summary, while the clinical significance of the p.Arg1263Trp variant is uncertain, these data suggest that it is more likely to be benign.
Ambry Genetics RCV000253530 SCV000319106 uncertain significance Cardiovascular phenotype 2016-07-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000628915 SCV000749823 uncertain significance Hypertrophic cardiomyopathy 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1263 of the MYBPC3 protein (p.Arg1263Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs370338674, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 181026). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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