Submissions for variant NM_000256.3(MYBPC3):c.2558del (p.Gly853fs)

dbSNP: rs397515977

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000473384	SCV000059159	pathogenic	Hypertrophic cardiomyopathy	2014-07-29	criteria provided, single submitter	clinical testing	The Gly853fs variant in MYBPC3 has been reported in one individual with HCM and was absent from 200 Caucasian and 200 Black control chromosomes (Van Driest 2004 - reported as I852fs/25, Bos 2014). This variant has also been identified by ou r laboratory in 2 Caucasian adults with HCM and segregated with disease in 2 aff ected relatives from one family. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 853 and l eads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein (loss of function). Loss of function is an established mechanism of disease for the MYBPC3 gene in p atients with HCM. In summary, this variant meets our criteria to be classified a s pathogenic (www.partners.org/personalizedmedicine/lmm) based on the severity o f the predicted impact.
GeneDx	RCV000158367	SCV000208302	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 26914223, 15519027, 24793961, 27532257, 28420666, 34135346)
Invitae	RCV000473384	SCV000546432	pathogenic	Hypertrophic cardiomyopathy	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly853Alafs*26) 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 (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42641). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000158367	SCV000928177	pathogenic	not provided	2019-01-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486549	SCV004239364	pathogenic	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing