ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.913_914del (p.Phe305fs) (rs397516080)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000488321 SCV000059328 pathogenic Hypertrophic cardiomyopathy 2013-09-26 criteria provided, single submitter clinical testing The Phe305fs variant in MYBPC3 has been reported in two individuals with HCM and was absent from 600 control chromosomes (Olivotto 2008; Millat 2010). It has al so now been identified by our laboratory in >5 Caucasian individuals with HCM an d segregated with disease in 3 affected relatives from 2 families. Data from la rge population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 305 and lead to a premature termination codon 26 amino aci ds downstream. This alteration is then predicted to lead to a truncated or absen t protein. Loss of function of the MYBPC3 gene is an established disease mechani sm in HCM. In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM).
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000035677 SCV000256178 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000208183 SCV000264049 pathogenic Primary familial hypertrophic cardiomyopathy 2015-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000489037 SCV000577575 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The c.913_914delTT pathogenic variant in the MYBPC3 gene has been reported as a founder mutation in an Italian cohort with 19 probands and was absent in 400 control alleles (Calore et al., 2015). In addition, the c.913_914delTT variant has previously been observed in two other individuals with HCM (Olivotto et al., 2008; Teirlinck et al., 2012). The c.913_914delTT variant is not observed in large population cohorts (Lek et al., 2016; 100 Genomes Consortium et al., 2015; Exome Variant Server). Moreover, it has been identified in individuals referred for HCM genetic testing at GeneDx.This variant causes a shift in reading frame starting at codon Phenylalanine 305, changing it to a Proline, and creating a premature stop codon at position 27 of the new reading frame, denoted p.Phe305ProfsX27. 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. Finally, other frameshift variants in the MYBPC3 gene have been reported in association with HCM.In summary, c.913_914delTT in the MYBPC3 gene is interpreted as a pathogenic variant.
Center for Human Genetics,University of Leuven RCV000488321 SCV000886750 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000489037 SCV000927717 pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000488321 SCV000996344 pathogenic Hypertrophic cardiomyopathy 2017-01-20 criteria provided, single submitter research The MYBPC3 Phe305Profs*27 has been previously reported in mulitple HCM patients (Calore C, et al., 2015; Marsiglia JD, et al., 2013; Teirlinck CH, et al., 2012; Millat G, et al., 2010, Olivotto I, et al., 2008), and is an established Italian founder (Calore C, et al., 2015). This variant has not identified in the 1000 genomes project (http://www.1000genomes.org/), or in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Our lab has identified this variant in 2 HCM probands both of which are of Italian descent. 1 proband harbours a second variant (CRYAB 324+5G>T). Familial screening did not reveal a family history of disease or SCD, therefore the significance of the second variant (CRYAB 324+5G>T) is undetermined. Loss of function mutations in MYBPC3 are an established cause of HCM. Therefore, we classify MYBPC3 Phe305Profs*27 as "pathogenic".
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196005 SCV001366434 pathogenic Hypertrophic cardiomyopathy; Hyperlipidemia 2019-02-21 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197763 SCV001368542 pathogenic Polycystic kidney dysplasia; Hypertrophic cardiomyopathy 2020-04-02 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.
OMIM RCV000035677 SCV000233280 pathogenic Familial hypertrophic cardiomyopathy 4 2015-05-01 no assertion criteria provided literature only
Rampazzo Lab, Human Molecular Genetics Unit,University of Padua RCV000488321 SCV000564398 pathogenic Hypertrophic cardiomyopathy 2017-04-18 no assertion criteria provided research It is not found in 250 ethnically matched healthy controls (500 chromosomes), in dbSNP , in the 1000 Genomes Project database, in the Exome Variant Server or in the Exome Aggregation Consortium. We identified this mutation in 19 (19.5%) italian HCM patients (14 men and 5 women). Among 79 relatives belonging to 14 families, 45 resulted to be mutation carriers and 29 of them had phenotypical expression of HCM. A shared haplotype was found in all probands carrying the mutation, indicating that a common founder was likely in these families.

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