Submissions for variant NM_000256.3(MYBPC3):c.1504del (p.Arg502fs)

dbSNP: rs1555122188

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599533	SCV000710370	likely pathogenic	not provided	2018-01-09	criteria provided, single submitter	clinical testing	Although the c.1504delC variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon arginine 502, changing it to a glycine, and creating a premature stop codon at position 11 of the new reading frame, denoted p.Arg502GlyfsX11. This 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. Other downstream frameshift variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), in a gene for which loss-of-function is a known mechanism of disease. Furthermore, the c.1504delC variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae	RCV001381034	SCV001579286	pathogenic	Hypertrophic cardiomyopathy	2020-01-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant has not been reported in the literature in individuals with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 504065). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg502Glyfs*11) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product.