Submissions for variant NM_000256.3(MYBPC3):c.3776del (p.Gln1259fs)

gnomAD frequency: 0.00001  dbSNP: rs727503166

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844679	SCV000198794	pathogenic	Left ventricular noncompaction; Hypertrophic cardiomyopathy	2012-09-24	criteria provided, single submitter	clinical testing	The Gln1259fs variant in MYBPC3 has not been reported in the literature, but has been identified in 3 families with cardiomyopathy tested by our laboratory (Del lefave 2009, LMM unpublished data). In one family, an infant with LVNC and DCM ( likely to be burnt-out HCM) also carried a de novo variant in MYH7, while the af fected mother (LVNC) carried this frameshift variant in isolation (Dellefave 200 9). In a second family, this frameshift variant was observed in isolation in ind ividuals with HCM, though some individuals carried a second likely disease-causi ng variant in MYH7 causing a spectrum of cardiomyopathies to be observed in the family (including HCM, DCM, LVNC, and ARVC; LMM unpublished data). This frameshi ft variant is predicted to alter the protein?s amino acid sequence beginning at position 1259 and lead to a premature termination codon 72 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of the MYBPC3 gene is an established disease mechan ism in HCM patients. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM)
GeneDx	RCV001706003	SCV000208344	likely pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Identified in an infant with LVNC who also harbored a de novo missense variant in the MYBPC3 gene; the c.3776delA variant was subsequently identified in the infant's mildly affected mother (Dellefave et al., 2009); Reported as a common pathogenic variant among individuals of Dutch background (Alimohamed et al., 2021); Frameshift variant predicted to result in protein truncation, as the last 16 amino acids are replaced with 71 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20019025, 22115648, 25611685, 27532257, 19666645, 29121657, 33532905, 26582918, 33500567, 33662488, 19808356, 30297972, 30847666, 20031619, 27535533, 23674513)
Ambry Genetics	RCV000621300	SCV000737354	pathogenic	Cardiovascular phenotype	2019-01-17	criteria provided, single submitter	clinical testing	The c.3776delA pathogenic mutation, located in coding exon 33 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3776. This deletion causes a translational frameshift that ablates the C-terminal 16 amino acids of myosin binding protein-C and replaces them with 72 spurious amino acids, which results in an elongated protein with an altered C-terminal domain (p.Q1259Rfs*72). This alteration was described in a proband with left ventricular non-compaction cardiomyopathy, who also had a de novo missense alteration in the second allele. The proband was reported to have no normal MYBPC3 protein expression and disorganized sarcomere M bands. This alteration was also present in the proband's mildly affected mother who was 28 years old at the time of examination (Dellefave LM et al. Circ Cardiovasc Genet. 2009;2:442-9). In another study, this alteration was detected in an individual with hypertrophic cardiomyopathy and two unaffected family members (Michels M et al. Eur Heart J. 2009;30:2593-8). In addition to the clinical data presented in the literature, this alteration is expected to be deleterious in nature. As such, this alteration is interpreted as a disease-causing mutation.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000600560	SCV000745024	pathogenic	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000628841	SCV000749748	pathogenic	Hypertrophic cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1259Argfs*72) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MYBPC3 protein. This variant is present in population databases (rs727503166, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with left ventricular noncompaction or hypertrophic cardiomyopathy (PMID: 19808356, 20019025, 20031619, 22115648, 25611685, 27532257, 29121657). ClinVar contains an entry for this variant (Variation ID: 164021). This variant disrupts a region of the MYBPC3 protein in which other variant(s) (p.Arg1271*) have been determined to be pathogenic (PMID: 18533079, 23396983, 27532257). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000151057	SCV000901751	pathogenic	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000600560	SCV001434954	pathogenic	Hypertrophic cardiomyopathy 4	2019-06-17	criteria provided, single submitter	clinical testing	The c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 23674513,25611685) or Left ventricular noncompaction (PMID 20031619) and is extremely rare in general population databases. Therefore, this c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000600560	SCV000733025	pathogenic	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001706003	SCV001922296	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001706003	SCV001926665	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001706003	SCV001958695	pathogenic	not provided		no assertion criteria provided	clinical testing