ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2776_2777CA[2] (p.Thr927fs) (rs727504265)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769314 SCV000900692 pathogenic Cardiomyopathy 2016-04-14 criteria provided, single submitter clinical testing
GeneDx RCV000158379 SCV000208314 pathogenic not provided 2016-11-10 criteria provided, single submitter clinical testing This mutation causes a shift in reading frame starting at codon Threonine 927, changing it to an Isoleucine, and creating a premature stop codon at position 123 of the new reading frame, denoted p.Thr927IlefsX123. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. The c.2780_2781delCA mutation in MYBPC3 has been observed in unrelated individuals tested for HCM at GeneDx. Moreover, numerous other frameshift mutations in the MYBPC3 gene have been reported in association with cardiomyopathy. In summary, c.2780_2781delCA in the MYBPC3 gene is interpreted as a disease-causing mutation.
Invitae RCV000229407 SCV000284232 pathogenic Hypertrophic cardiomyopathy 2018-02-07 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 27 of the MYBPC3 mRNA (c.2780_2781delCA), causing a frameshift at codon 927. This creates a premature translational stop signal (p.Thr927Ilefs*123) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in the literature in an individual with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177660). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000229407 SCV000203903 pathogenic Hypertrophic cardiomyopathy 2014-05-15 criteria provided, single submitter clinical testing The Thr927fs variant in MYBPC3 has not been previously reported in individuals w ith cardiomyopathy. Data from large population studies is insufficient to assess the frequency of this variant. The Thr927fs variant in MYBPC3 has been identifi ed by our laboratory in 1 Caucasian adult with HCM and segregated with disease i n at least 2 affected relatives. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 927 and l eads to a premature termination codon 123 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Heterozygous loss- of-function of the MYBPC3 gene is an established disease mechanism in individual s with HCM. In summary, this variant meets our criteria to be classified as path ogenic (http://pcpgm.partners.org/LMM) based on the predicted impact of the vari ant.

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