Submissions for variant NM_000256.3(MYBPC3):c.450del (p.Asp151fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158410	SCV000208345	likely pathogenic	not provided	2016-01-14	criteria provided, single submitter	clinical testing	Although the c.450delC likely pathogenic variant in the MYBPC3 gene has not been reported to our knowledge, this variant has previously been identified in one other unrelated individual who underwent genetic testing for HCM at GeneDx. The c.450delC variant causes a shift in reading frame starting at codon Aspartic Acid 151, changing it to a Methionine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Asp151MetfsX8. This likely 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. Multiple other downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, the c.450delC variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.450delC in the MYBPC3 gene is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype.
Invitae	RCV001203794	SCV001374971	pathogenic	Hypertrophic cardiomyopathy	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp151Metfs*8) 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181105). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003147373	SCV003835457	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-08-24	criteria provided, single submitter	clinical testing

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