Submissions for variant NM_000256.3(MYBPC3):c.2534_2538del (p.Arg845fs)

dbSNP: rs397515973

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035503	SCV000059153	pathogenic	Hypertrophic cardiomyopathy	2011-09-21	criteria provided, single submitter	clinical testing	The Arg845fs variant has been reported in the literature in 1 family with HCM, w as absent from 400 control chromosomes, and segregated with disease in 5 affecte d family members (Carrier 1997, Richard 2003). In addition, this variant is pre dicted to cause a frameshift, which alters the protein's amino acid sequence beg inning at codon 845 and leads to a premature stop codon 37 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. Loss of function is an established mechanism of disease for the MYBPC3 gene. Th erefore, the Arg845fs variant meets our criteria for pathogenicity (http://pcpgm .partners.org/lmm) based on segregation, absence in controls, and impact of the variant.
GeneDx	RCV000158478	SCV000208413	pathogenic	Cardiomyopathy	2012-02-10	criteria provided, single submitter	clinical testing	A deletion of 5 nucleotides in exon 25 of the MYBPC3 gene. The normal sequence with the bases that are deleted in braces is: ATGC{GCGTC}TACG. This mutation is denoted c.2534_2538delGCGTC at the cDNA level or at the protein level as p.Arg845LeufsX37. The c.2534_2538delGCGTC mutation in the MYBPC3 gene has been reported previously in one individual with HCM and it was not present in 200 control chromosomes (Richard P, 2003). The c.2534_2538delGCGTC mutation causes a shift in reading frame starting at codon Arginine 845, changing it to a Leucine, and creates a premature stop codon at position 37 of the new reading frame. This mutation is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000035503	SCV003440373	pathogenic	Hypertrophic cardiomyopathy	2022-08-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg845Leufs*37) 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: 9048664, 27532257). This variant is also known as c.2566_2570del. ClinVar contains an entry for this variant (Variation ID: 42635).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000158478	SCV003838270	pathogenic	Cardiomyopathy	2022-03-11	criteria provided, single submitter	clinical testing
OMIM	RCV000009142	SCV000029359	pathogenic	Hypertrophic cardiomyopathy 4	1997-03-01	no assertion criteria provided	literature only