Submissions for variant NM_000256.3(MYBPC3):c.3476_3479dup (p.Pro1161fs)

dbSNP: rs397516019

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035589	SCV000059240	pathogenic	Hypertrophic cardiomyopathy	2011-06-02	criteria provided, single submitter	clinical testing	The Pro1161fs variant has not been reported in the literature but has been detec ted in 1 individual with HCM tested by our laboratory. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1161 and leads to a premature stop codon 8 amino acids downstream. This alterat ion 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, which makes it highly likely that the Pro1161fs variant is pathogenic.
GeneDx	RCV000158404	SCV000208339	pathogenic	not provided	2013-05-29	criteria provided, single submitter	clinical testing	Although the c.3476_3479dupTTAT variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 1161, changing it to a Tyrosine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Pro1161TyrfsX9. This 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 frameshift variants in the MYBPC3 gene have been reported in association with HCM. In summary, c.3476_3479dupTTAT in the MYBPC3 gene is interpreted as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000035589	SCV003270418	pathogenic	Hypertrophic cardiomyopathy	2022-05-18	criteria provided, single submitter	clinical testing	This variant is also known as as c.3476-3479dupTTAT (p.Ile1160Ilefs*10). This premature translational stop signal has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1161Tyrfs*9) 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). ClinVar contains an entry for this variant (Variation ID: 42714). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149619	SCV003838929	pathogenic	Cardiomyopathy	2021-11-11	criteria provided, single submitter	clinical testing