ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.833del (p.Gly278fs) (rs727503212)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000470757 SCV000198946 pathogenic Hypertrophic cardiomyopathy 2013-05-31 criteria provided, single submitter clinical testing The Gly278fs variant in MYBPC3 has not been reported in individuals with cardiom yopathy. Data from large population studies is insufficient to assess the freque ncy of this variant. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 278 and lead to a premature terminati on codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in MYBPC3 are established as pathogenic for HCM. In summary, this variant meets our criteria to be classifie d as pathogenic ( based upon the predicted impact of the variant.
GeneDx RCV000158419 SCV000208354 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing The c.833delG pathogenic variant in the MYBPC3 gene has been previously reported in association with HCM (Bos et al., 2014; Walsh et al., 2017). In addition, this variant has been observed in multiple unrelated individuals referred for HCM testing at GeneDx. The c.833delG variant causes a shift in reading frame starting at codon glycine 278, changing it to a glutamic acid, and creating a premature stop codon at position 22 of the new reading frame, denoted p.Gly278GlufsX22. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, the c.833delG variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Blueprint Genetics RCV000208471 SCV000264048 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-04-08 criteria provided, single submitter clinical testing
Invitae RCV000470757 SCV000546483 pathogenic Hypertrophic cardiomyopathy 2020-08-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly278Glufs*22) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 164140). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617562 SCV000740244 pathogenic Cardiovascular phenotype 2019-05-06 criteria provided, single submitter clinical testing The c.833delG pathogenic mutation, located in coding exon 8 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 833, causing a translational frameshift with a predicted alternate stop codon (p.G278Efs*22). This mutation has been reported in an individual with hypertrophic cardimyopathy (HCM) and in HCM cohorts with limited details provided (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Blueprint Genetics RCV000158419 SCV000927927 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851294 SCV000993571 pathogenic Familial hypertrophic cardiomyopathy 4 2018-12-10 criteria provided, single submitter research
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000470757 SCV000995127 pathogenic Hypertrophic cardiomyopathy 2017-03-17 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158419 SCV000280282 likely pathogenic not provided 2014-03-03 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly278GlufsX22 Upon initial review, we considered this variant very likely disease causing, given that there is strong evidence that frameshift variants in MYBPC3 cause cardiomyopathy. This variant has not been reported in published literature (as of 1/27/2012), however it is very likely to cause disease because the deletion of the Guanine nucleotide at position 833 causes a shift in the reading frame, changing the amino acid sequence and creating a premature stop codon. This would be predicted to either lead to a truncated protein or a no protein production due to nonsense-mediate mRNA decay. Both protein truncating and null variants in MYBPC3 have been associated with cardiomyopathy. This variant is not listed in dbSNP or 1000 genomes (as of 1/27/2012). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~4,700 Caucasian and African American individuals (as of 1/27/2012). However, a missense variant at that same codon is present in 1/3308 Caucasians and 47/1629 African-Americans. Given these data, we think it is likely that this variant causes cardiomyopathy.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000470757 SCV001430857 likely pathogenic Hypertrophic cardiomyopathy 2019-05-28 no assertion criteria provided research This variant has been identified in 1 HCM proband as part of our research program. The variant also segregated to an affected third-degree family member (3 meiosis). For further information please feel free to contact us.

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