Submissions for variant NM_000256.3(MYBPC3):c.1641_1642del (p.Tyr548fs)

dbSNP: rs398123279

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078449	SCV000110302	pathogenic	not provided	2013-11-12	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000629016	SCV000198888	pathogenic	Hypertrophic cardiomyopathy	2014-08-22	criteria provided, single submitter	clinical testing	The Tyr548fs variant in MYBPC3 has previously been reported in at least 1 indivi dual with HCM and was absent from 400 control chromosomes (Driest 2004). Data fr om large population studies is insufficient to assess the frequency of this vari ant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 548 and leads to a premature terminat ion codon 19 amino acids downstream. This alteration is then predicted to lead t o a truncated or absent protein. Heterozygous loss of function of function of th e MYBPC3 gene is an established disease mechanism in HCM. In summary, this varia nt meets our criteria to be classified as pathogenic (http://www.partners.org/pe rsonalizedmedicine/LMM) based upon the predicted impact of the variant.
GeneDx	RCV000078449	SCV000208283	pathogenic	not provided	2024-09-25	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 15519027, 24111713, 33673806); 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: 33673806, 15519027, 24111713, 28971120, 29169752, 37937776, 37652022, 35653365)
Blueprint Genetics	RCV000208043	SCV000264054	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2015-10-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629016	SCV000749926	pathogenic	Hypertrophic cardiomyopathy	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr548Profs*19) 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: 15519027, 24111713, 28971120). This variant is also known as E546 fs/19. ClinVar contains an entry for this variant (Variation ID: 92689). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002399468	SCV002709351	pathogenic	Cardiovascular phenotype	2018-08-25	criteria provided, single submitter	clinical testing	The c.1641_1642delGT pathogenic mutation, located in coding exon 18 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 1641 to 1642, causing a translational frameshift with a predicted alternate stop codon (p.Y548Pfs*19). This variant has been previously reported in several hypertrophic cardiomyopathy cohorts (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60). In addition to the clinical data in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
deCODE genetics, Amgen	RCV003485535	SCV004022230	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-07-21	no assertion criteria provided	research	The variant NM_000256.3:c.1641_1642del (chr11:47342138) in MYBPC3 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as likely pathogenic.