ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.177_187del (p.Glu60fs) (rs397515925)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000461041 SCV000059080 pathogenic Hypertrophic cardiomyopathy 2019-02-01 criteria provided, single submitter clinical testing The p.Glu60AlafsX49 variant in MYBPC3 has been reported in 9 individuals with HCM (7 individuals: Zimmerman 2010, Alfares 2015, Walsh 2016; 1 individual: Burns 2016; 1 individual: Murphy 2017) and segregated with disease in 1 affected (LMM data). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 42565). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 60 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate.
GeneDx RCV000158384 SCV000208319 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing The c.177_187del11 pathogenic variant in the MYBPC3 gene was reported in an individual whosesample served as a positive control in a DNA sequencing array validation study; however, clinical andfamily history information for this individual were not provided (Zimmerman et al., 2010). Moreover,c.177_187del11 has been seen in multiple individuals referred for HCM testing at GeneDx and isclassified as a pathogenic variant by two other clinical laboratories in ClinVar (SCV000059080.3,SCV000219627.1; Landrum et al., 2016). The c.177_187del11 variant in the MYBPC3 gene causes ashift in reading frame starting at codon Glutamic acid 60, changing it to an Alanine, and creates apremature stop codon at position 49 of the new reading frame, denoted p.Glu60AlafsX49. This changeis expected to result in an abnormal, truncated protein or an absence of protein from this allele due tomRNA decay. Other frameshift pathogenic variants in the MYBPC3 gene have been reported inassociation with HCM (Stenson et al., 2014). Furthermore, the c.177_187del11 variant was notobserved in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.177_187del11 in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000461041 SCV000546433 pathogenic Hypertrophic cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing This sequence change deletes 11 nucleotides from exon 2 of the MYBPC3 mRNA (c.177_187delAGAGGGCACAC), causing a frameshift at codon 60. This creates a premature translational stop signal (p.Glu60Alafs*49) and is expected to result in an absent or disrupted protein product. Truncating variants in MYBPC3 are known to be pathogenic. This particular truncation has been reported in at least one individual affected with dilated cardiomyopathy (PMID: 20474083). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586702 SCV000696319 pathogenic Cardiovascular phenotype 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.177_187delAGAGGGCACAC (p.Glu60Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (e.g. c.324delT (p.Ala109fs), c.436dupA (p.Thr146fs), and c.484C>T (p.Gln162X)). The variant of interest was absent in 52540 control chromosomes. Multiple publications have cited the variant in affected individuals (HCM), along with a clinical diagnostic laboratory citing the variant to have occurred in 16 affected individuals (7 families), which 1 family showed segregation with disease (via ClinVar - Partners). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000586702 SCV000740078 pathogenic Cardiovascular phenotype 2018-07-11 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Heart Center,Academic Medical Center Amsterdam RCV000850018 SCV000992160 likely pathogenic Left ventricular noncompaction 10 2018-12-01 criteria provided, single submitter research
Color RCV001188337 SCV001355374 pathogenic Cardiomyopathy 2019-10-28 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000461041 SCV001430858 pathogenic Hypertrophic cardiomyopathy 2015-07-01 no assertion criteria provided research MYBPC3 Glu60Alafs*49 has been observed previously >10 probands with HCM (Walsh et al., 2017; Kapplinger et al., 2014) and has also been reported in a DCM case (Zimmerman et al, 2010). It is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this MYBPC3 Glu60Alafs*49 in a HCM proband and the variant was found to segregate to two affected family members (Ingles et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been seen reported in more than 10 unrelated HCM probands (PS4) and is rare in the general population (PM2), therefore we classify MYBPC3 Glu60Alafs*49 as "Pathogenic".

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