Submissions for variant NM_000256.3(MYBPC3):c.436dup (p.Thr146fs)

gnomAD frequency: 0.00001  dbSNP: rs397516049

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000693262	SCV000059277	pathogenic	Hypertrophic cardiomyopathy	2013-08-02	criteria provided, single submitter	clinical testing	The Thr146fs variant in MYBPC3 was identified in three individuals with HCM from two families by our laboratory. This frameshift variant is predicted to alter t he protein?s amino acid sequence beginning at position 146 and lead to a prematu re termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in the MYBPC3 gen e are established as pathogenic for HCM. In summary, this variant meets our crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon a bsence from controls and loss of function of the MYBPC3 gene.
GeneDx	RCV000414699	SCV000490633	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in the published literature (Alfares et al., 2015; Murphy et al., 2016; Walsh et al., 2017); also known as c.436_437insA due to alternate nomenclature; 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: 27532257, 26914223, 25611685)
Invitae	RCV000693262	SCV000821123	pathogenic	Hypertrophic cardiomyopathy	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr146Asnfs*7) 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 present in population databases (rs397516049, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42751). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769363	SCV000900751	pathogenic	Cardiomyopathy	2021-07-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307373	SCV002600334	pathogenic	Primary familial hypertrophic cardiomyopathy	2022-10-07	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.436dupA (p.Thr146AsnfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 167712 control chromosomes. c.436dupA has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Murphy_2016, Alfares_2015, Ho_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002326724	SCV002628685	pathogenic	Cardiovascular phenotype	2022-03-07	criteria provided, single submitter	clinical testing	The c.436dupA pathogenic mutation, located in coding exon 4 of the MYBPC3 gene, results from a duplication of A at nucleotide position 436, causing a translational frameshift with a predicted alternate stop codon (p.T146Nfs*7). This alteration has been reported in hypertrophic cardiomyopathy (HCM) genetic testing cohorts; however, clinical details were limited (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented 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.