Submissions for variant NM_000256.3(MYBPC3):c.2556del (p.Ile852fs)

dbSNP: rs727503186

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151091	SCV000198846	pathogenic	Hypertrophic cardiomyopathy	2013-05-16	criteria provided, single submitter	clinical testing	The Ile852fs variant in MYBPC3 has been reported in 1 individual with HCM (Richa rds 2003). This frameshift variant is predicted to alter the protein?s amino aci d sequence beginning at position 852 and lead to a premature termination codon 2 7 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Truncating variants in MYBPC3 are established as pathogeni c for HCM. In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM) based on the predicted impact of the varia nt.
GeneDx	RCV000158370	SCV000208305	pathogenic	not provided	2012-06-03	criteria provided, single submitter	clinical testing	The c.2556delC variant in the MYBPC3 gene has been reported in association with HCM (Richard P et al., 2003). Richard et al. identified c.2556delC (reported as del C16212 using alternative nomenclature) in one patient with HCM, and the mutation was absent in 200 control chromosomes. The c.2556delC variant causes a shift in the reading frame starting at codon Isoleucine 852, changing it to a Methionine, and creates a premature stop codon at position 27 of the new reading frame. This variant is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. Therefore, c.2556delC in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae	RCV000151091	SCV003270423	pathogenic	Hypertrophic cardiomyopathy	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile852Metfs*27) 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 individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 26914223). This variant is also known as Del C16212. ClinVar contains an entry for this variant (Variation ID: 164071). For these reasons, this variant has been classified as Pathogenic.