ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2096del (p.Pro699fs)

dbSNP: rs397515947
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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, Mass General Brigham Personalized Medicine RCV000232610 SCV000059112 pathogenic Hypertrophic cardiomyopathy 2017-11-28 criteria provided, single submitter clinical testing The p.Pro699fs variant (also referred to as Ala698fs and A698fs54) in MYBPC3 has been reported in 8 individuals with HCM and segregated with disease in 5 affect ed family members (Nimura 1998, Van Driest 2004, Wilson 2011, Bos 2014, LMM data ). It has not been identified in large population studies. This variant is predi cted to cause a frameshift, which alters the protein?s amino acid sequence begin ning at position 699 and leads to a premature termination codon 55 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic b ased upon segregation studies, absence from controls, and the predicted impact t o the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate.
GeneDx RCV000158358 SCV000208293 pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 42596; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15114369, 25351510, 9562578, 24793961, 15519027, 22122802, 26743238, 26914223, 27532257, 28615295, 31006259, 23549607, 33087929)
Invitae RCV000232610 SCV000284219 pathogenic Hypertrophic cardiomyopathy 2023-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro699Glnfs*55) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 15519027, 22122802, 24793961, 26914223). It has also been observed to segregate with disease in related individuals. This variant is also known as delC698 and A698fs/54. ClinVar contains an entry for this variant (Variation ID: 42596). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000158358 SCV000927791 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000853466 SCV000996377 pathogenic Primary dilated cardiomyopathy; Hypertrophic cardiomyopathy 2017-08-01 criteria provided, single submitter research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170424 SCV001333002 pathogenic Cardiomyopathy 2021-06-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001170424 SCV001735650 pathogenic Cardiomyopathy 2023-06-09 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 22 in the Ig-like domain C5 of the MYBPC3 gene (also known as DelC698 and A698 fs/54 in the literature), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 15519027, 20031618, 22122802, 23549607, 24793961, 25351510, 26914223, 27532257, 28408708, 32731933, 32841044, 33495597, 34310159; Color internal data). It has been shown that this variant segregates with disease in multiple affected individuals across 2 families (PMID: 9562578, 22122802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000158358 SCV002103240 pathogenic not provided 2021-06-29 criteria provided, single submitter clinical testing PVS1, PM2, PS4_moderate, PP1
Genetics and Molecular Pathology, SA Pathology RCV002466417 SCV002761681 pathogenic Hypertrophic cardiomyopathy 4 2021-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV003352753 SCV004080085 pathogenic Cardiovascular phenotype 2023-08-07 criteria provided, single submitter clinical testing The c.2096delC pathogenic mutation, located in coding exon 22 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 2096, causing a translational frameshift with a predicted alternate stop codon (p.P699Qfs*55). This mutation has been reported in multiple individuals and families with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Wilson MG et al. J Cardiovasc Magn Reson, 2011 Nov;13:77; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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