ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3288del (p.Glu1096fs) (rs727503172)

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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 RCV000540054 SCV000198811 pathogenic Hypertrophic cardiomyopathy 2014-08-06 criteria provided, single submitter clinical testing The p.Glu1096fs variant in MYBPC3 has been identified in 5 individuals with HCM (Lekanne Deprez 2006, Kapplinger 2014, LMM unpublished data). It was absent from large population studies. This variant is predicted to cause a frameshift, whic h alters the protein?s amino acid sequence beginning at position 1096 and lead t o a premature termination codon 93 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criteria to be classified as pathogenic (http://www.partn ers.org/personalizedmedicine/LMM) based upon the predicted impact of the variant .
GeneDx RCV000158396 SCV000208331 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The c.3288delG pathogenic variant in the MYBPC3 gene has been reported previously in association with HCM (Lekanne Deprez et al., 2006; Waldmuller et al., 2011; Kapplinger et al., 2014). This variant causes a shift in reading frame starting at codon glutamic acid 1096, changing it to an aspartic acid, and creating a premature stop codon at position 93 of the new reading frame, denoted p.Glu1096AspfsX93. Lekanne Deprez et al. (2006) identified c.3288delG (reported as c.3288delA due to the polymorphism c.3288 G>A) in one infant with severe, neonatal HCM who was compound heterozygous for a second truncating variant in the MYBPC3 gene. This patient was confirmed to inherit c.3288delG from his mother, who had a family history of HCM in two relatives. Of note, this patient and his mother also harbored the R589H variant of unknown significance in the MYBPC3 gene, which was on the same allele (in cis) as the c.3288delG pathogenic variant, limiting the interpretation of the clinical significance of this missense change (Lekanne Deprez et al., 2006). This report noted that RNA studies in the patient's mother indicated c.3288delG results in a premature termination codon and absence of protein from this allele due to mRNA nonsense mediated decay. Waldmuller et al. (2011) also identified the c.3288delG pathogenic variant in one Caucasian individual diagnosed with HCM. Moreover, Kapplinger et al. (2014) observed this variant in three additional individuals diagnosed with HCM and it was found to be absent from 854 control alleles. Additionally, other frameshift variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.3288delG pathogenic variant is not observed in large population cohorts (Lek et al., 2016).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000158396 SCV000229295 pathogenic not provided 2014-10-23 criteria provided, single submitter clinical testing
Invitae RCV000540054 SCV000623585 pathogenic Hypertrophic cardiomyopathy 2019-06-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1096Aspfs*93) 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 observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 24510615, 2732257, 16679492, 21750094). ClinVar contains an entry for this variant (Variation ID: 164042). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587552 SCV000696328 pathogenic Cardiovascular phenotype 2016-01-11 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a frameshift mutation resulting in a predicted truncated MYBPC3 protein. Mutation taster predicts disease causing outcome for this deletion. The variant is absent from the large and broad cohorts of the ExAC project while it was observed in HCM patients indicating a deleterious outcome. Additionally, there is unaffected carriers reported in the literature suggesting incomplete penetrance (Lekanne_2006). Lekanne_2006 assessed the effect of the variant on mRNA expression. They investigated RNA isolated from peripheral blood from a variant carrier and could not detect the variant, indicating the mRNA harboring the variant of interest to undergo nonsense mediated mRNA decay (NMD) further supporting a disease causing impact. Moreover, clinical diagnostic laboratories classify variant as Pathogenic via ClinVar. Considering all evidence, the variant was classified as a Pathogenic.
Ambry Genetics RCV000587552 SCV000740080 pathogenic Cardiovascular phenotype 2016-11-29 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769309 SCV000900687 pathogenic Cardiomyopathy 2017-08-04 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000540054 SCV000995121 pathogenic Hypertrophic cardiomyopathy 2019-04-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000151070 SCV001428853 uncertain significance Familial hypertrophic cardiomyopathy 4 2018-10-02 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000151070 SCV000733029 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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