ClinVar Genomic variation as it relates to human health

Variant summary: MYBPC3 c.3742_3759dup18 (p.Gly1248_Cys1253dup) results in an in-frame duplication that is predicted to duplicate six amino acids into the encoded protein. The variant was absent in 250026 control chromosomes. c.3742_3759dup18 has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Watkins_1995, Ho_2013, Helms_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence suggests that the variant has an effect on protein stability (e.g. Brown_2002, Helms_2014).. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The MYBPC3 c.3742_3759dup; p.Gly1248_Cys1253dup variant (rs193922384), also published as ins18bp1163, is reported in the literature in multiple individuals and families affected with hypertrophic cardiomyopathy or dilated cardiomyopathy (Helms 2014, Maron 2001, Kapplinger 2014, Watkins 1995, Zimmerman 2010). The variant was observed to co-segregate with disease in at least one large kindred (Watkins 1995). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant duplicates six amino acid residues, leaving the rest of the protein in-frame. Functional studies from multiple groups suggest the variant protein is unstable relative to the wildtype protein (Brown 2002, Glazier 2018, Helms 2014). Based on available information, this variant is considered to be pathogenic. References: Brown LJ et al. Functional and spectroscopic studies of a familial hypertrophic cardiomyopathy mutation in Motif X of cardiac myosin binding protein-C. Eur Biophys J. 2002 Sep;31(5):400-8. Glazier AA et al. HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C. JCI Insight. 2018 Jun 7;3(11):e99319. Helms AS et al. Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2014 Aug;7(4):434-43. Kapplinger JD et al. Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61. Maron BJ et al. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol. 2001 Aug;38(2):315-21. Watkins H et al. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet. 1995 Dec;11(4):434-7. Zimmerman RS et al. A novel custom resequencing array for dilated cardiomyopathy. Genet Med. 2010 May;12(5):268-78.

The c.3742_3759dup (p.Gly1248_Cys1253dup) variant duplicates 18 nucleotides in exon 33 of the MYBPC3 gene, leading to an in-frame duplication of 6 amino acid residues in the C-terminal Ig-like domain of the MYBPC3 protein. This variant has been reported in almost twenty individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 7493025, 11499718, 20474083, 23549607, 24510615, 27532257), as well as in an individual affected with dilated cardiomyopathy (DCM) (PMID: 20474083). It has also been observed to segregate with disease in 7 related individuals from a family affected with HCM (PMID: 7493025). In vitro experimental studies suggest that this in-frame variant affects the expression and structural stability of the MYBPC3 protein (PMID: 25031304, 12202917, 29875314). This variant has not been identified in the general population according to the Genome Aggregation Database (gnomAD). Based on these evidence, the c.3742_3759dup (p.Gly1248_Cys1253dup) variant in MYBPC3 gene is interpreted as pathogenic.

proposed classification - variant undergoing re-assessment, contact laboratory

PS3, PS4_moderate, PM2, PM4, PP1_strong,

The c.3742_3759dup18 pathogenic mutation (also known as p.G1248_C1253dup) is located in coding exon 33 of the MYBPC3 gene. This variant results from an in-frame duplication of 18 nucleotides at positions 3742 to 3759. This results in the duplication of six residues between codons 1248 and 1253. This alteration has been detected in multiple individuals reported to have hypertrophic cardiomyopathy and has been reported to segregate with disease in at least one family (Watkins H et al. Nat Genet. 1995;11:434-7 (reported as 18bp tandem duplication of residues 3774-3791); Maron BJ et al. J Am Coll Cardiol. 2001 Aug;38:315-21 (reported as ins18bp1163); Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61). Functional studies performed in vitro and ex vivo suggest that this duplication results in a mislocalized, unstable protein subject to rapid degradation (Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Glazier AA et al. JCI Insight 2018 Jun;3(11)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Identified in multiple individuals with HCM in published literature, also reported as Ins18bp1163 due to alternate nomenclature (Watkins et al., 1995; Maron et al., 2001; Kapplinger et al., 2014; Walsh et al., 2017), and identified in multiple individuals referred for HCM genetic testing at GeneDx.; Not observed at significant frequency in large population cohorts (gnomAD); In-frame duplication of six amino acid residues (Gly, Gly, Ile, Tyr, Val, Cys), which is predicted to disrupt protein structure and stability (Watkins et al., 1995; Brown et al., 2002; Helms et al., 2014); Published functional study demonstrates the absence of mutant protein in septal myectomy and transplant tissue, suggesting this duplication may destabilize the protein and lead to haploinsufficiency (Helms et al., 2014; Helms et al., 2020); In-frame duplication of six amino acid residues (Gly, Gly, Ile, Tyr, Val, Cys), which is predicted to disrupt protein structure and stability (Watkins et al., 1995; Brown et al., 2002; Helms et al., 2014); This variant is associated with the following publications: (PMID: 12202917, 25714468, 24510615, 27532257, 29875314, 25031304, 7493025, 32841044, 15519027, 11499718)

This variant (also known as ins18bp1163) duplicates 18 nucleotides in exon 33 of the MYBPC3 gene, which leads to the duplication of 6 amino acid residues in the in the C-terminal Ig-like domain of the MYBPC3 protein. A functional study has shown that the variant affects protein stability (PMID: 25031304). This variant has been reported in over twenty individuals affected with or suspected of having hypertrophic cardiomyopathy (PMID: 7493025, 11499718, 23549607, 24510615, 27532257; https://doi.org/10.1161/circ.142.suppl_3.15632; communication with an external laboratory, ClinVar SCV000203962.4). This variant has been shown to segregate with hypertrophic cardiomyopathy in at least ten individuals from multiple families (PMID: 7493025; communication with an external laboratory, ClinVar SCV000203962.4). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This variant, c.3742_3759dup, results in the insertion of 6 amino acid(s) of the MYBPC3 protein (p.Gly1248_Cys1253dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 7493025, 20474083, 23549607, 24510615, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8603). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MYBPC3 function (PMID: 12202917, 25031304). For these reasons, this variant has been classified as Pathogenic.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly1248_Cys1253dup Based on the data reviewed below we consider this variant likely disease-causing. This variant has been seen in at least 5 unrelated families with HCM, with strong segregation data in one family and moderate segregation data in another unrelated family. This was one of the variants reported when the Seidman group first linked HCM to MYBPC3 (Watkins et al 1995). In total, the variant was present in 7 affected family members (including 5 with clinical diagnoses of HCM, and 2 younger family members with findings consistent with the disease but without evidence of LVH on echo (abnormal EKG and systolic anterior motion of the mitral valve)) for a lod score of 2.32. Absent from 100 controls. Maron et al. 2001 reported this variant in one family with HCM, where it is referred to as Ins18bp1163. It appears that this is a different family from that presented in Watkins et al. 1995, however there are not specific details presented with regard to segregation or phenotype of this family in Maron 2001 thus not possible to say with certainty. Ho et al. 2013 studied a cohort of sarcomeric gene mutation carriers with HCM with and without LVH, and this duplication was present in one subject with HCM (however no details are presented thus it is difficult to confirm whether this represents an unrelated case of HCM). This variant results in an 18 base pair, in frame, tandem repeat of nucleotides 3774 to 3791 in the penultimate exon of the gene (c-terminal immunoglobulin domain, specifically motif 10 that is responsible for binding the myosin rod and titin). This leads to the tandem duplication of six amino acids (GlyGlyIleTyrValCys). It is expected to disrupt one of the seven beta sheets that form the canonical 3-dimensional barrel structure of the c-terminal myosin-binding region of the protein (Watkins et al. 1995). Brown et al (2002) studied the mutant protein in vitro and found that it was less stable than wildtype. They did not observe any differences in binding to myosin. Molecular modeling suggested that the duplicated amino acids were in fact not directly involved in myosin binding, and authors postulated instead may affect some other function of Motif 10, possibly its binding to titin or an alteration in an interaction that may occur with Motif 7 or the adjacent Motif 9. (Oakley et al. 2004). There are no available in silico prediction programs that can query an insertion of 18 bp at this point (Mutation Taster at present only handles indels up to 12 bases). In frame indels have been reported throughout MYBPC3 in association with cardiomyopathy in the literature. In total, this variant has not been seen in ~6,100 published control samples and individuals available from population datasets. Not present in the NHLBI Exome Sequencing dataset, which currently includes ~6,000 individuals of Caucasian and African American ancestries. Of note, however, while this database does now include insertions/deletions, exome sequencing is limited when detecting larger indels and it is possible that an 18-bp insertion could be missed. It is also not present in the ExAC database, which includes ~65,000 individuals of varying ancestries from the general population (as of December 2014).

Variant classified as Pathogenic and reported on 11-03-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.