Submissions for variant NM_000256.3(MYBPC3):c.3226_3227insT (p.Asp1076fs)

gnomAD frequency: 0.00001  dbSNP: rs397516008

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000470975	SCV000059217	pathogenic	Hypertrophic cardiomyopathy	2019-08-14	criteria provided, single submitter	clinical testing	The p.Asp1076ValfsX6 variant in MYBPC3 has been reported in >20 individuals with HCM and segregated with disease in 3 affected individuals from 3 families (Bos 2014, Kapplinger 2014, Walsh 2017, LMM data). It has also been identified in 1/15396 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1076 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1.
GeneDx	RCV000158395	SCV000208330	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42694; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28152038, 24510615, 24793961, 25611685, 26688388, 25031304, 20800588, 24721642, 27532257, 20474083, 31006259, 30550750, 33087929)
Ambry Genetics	RCV000252468	SCV000318828	pathogenic	Cardiovascular phenotype	2021-06-18	criteria provided, single submitter	clinical testing	The c.3226_3227insT pathogenic mutation, located in coding exon 30 of the MYBPC3 gene, results from an insertion of one nucleotide at position 3226, causing a translational frameshift with a predicted alternate stop codon (p.D1076Vfs*6). This alteration has previously been described in individuals reported to have hypertrophic cardiomyopathy (HCM) (Bos JM et al. Mayo Clin Proc. 2014;89:727-37). This variant was also observed in multiple individuals from HCM genetic testing cohorts; however, clinical details were limited (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.
Invitae	RCV000470975	SCV000546397	pathogenic	Hypertrophic cardiomyopathy	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1076Valfs*6) 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 cardiomyopathy (PMID: 20474083, 24510615, 25031304, 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 42694). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000158395	SCV000927282	pathogenic	not provided	2017-06-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176298	SCV001340215	pathogenic	Cardiomyopathy	2023-05-04	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 30 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause mislocalization of the MYBPC3 protein within the sarcomere and decreased incorporation into myofilament (DOI:10.1161/circ.130.suppl_2.20311). This variant has been reported in over twenty individuals affected with hypertrophic cardiomyopathy (PMID: 24510615, 25031304, 25611685, 27532257, 31006259, 32841044, 33495596, 33495597). It has also been reported in individuals affected with dilated cardiomyopathy (PMID: 20474083). This variant has been identified in 1/31354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176298	SCV004239374	pathogenic	Cardiomyopathy	2022-06-30	criteria provided, single submitter	clinical testing