ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3742_3759dup (p.Gly1248_Cys1253dup) (rs193922384)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000463609 SCV000203962 pathogenic Hypertrophic cardiomyopathy 2015-06-09 criteria provided, single submitter clinical testing The p.Gly1248_Cys1253dup variant in MYBPC3 has been identified in >20 individual s with HCM and segregated with disease in 9 affected family members from 3 famil ies (Watkins 1995, Maron 2001, Helms 2014, Kapplinger 2014; LMM unpublished data ). This variant is a duplication of 6 amino acids after position 1253 and is not predicted to alter the protein reading-frame. In-vitro functional studies provi de some evidence that the p.Gly1248_Cys1253dup variant may impact protein functi on (Brown 2002, Helms 2014); however, these types of assays may not accurately r epresent biological function. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segr egation studies and impact to the protein.
GeneDx RCV000223778 SCV000208341 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing The c.3742_3759dupGGGGGCATCTATGTCTGC variant in the MYBPC3 gene has been reported in association with HCM (Watkins et al., 1995; Maron et al., 2001; Kapplinger et al., 2014). The c.3742_3759dup18 variant has also been reported as Ins18bp1163 due to alternative nomenclature (Maron et al., 2001). Watkins et al. (1995) identified c.3742_3759dup18 in a family with HCM and the variant co-segregated with disease in multiple family members and was absent from 200 control chromosomes. This variant has also been reported by an outside laboratory to segregate with disease in three family members from two families (Landrum et al., 2014). Furthermore, this variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although Van Driest et al. (2004) reported c.3742_3759dup18 in 1% of control alleles, post-publication communication with these authors revealed this variant was not truly present in their control cohort (pers. comm. 6/2013). The c.3742_3759dup18 variant results in a duplication of six amino acids (GlyGlyIleTyrValCys) which is predicted to disrupt protein structure and stability (Watkins et al., 1995; Brown et al., 2002; Helms et al., 2014). Helms et al. (2014) demonstrated that c.3742_3759dup18 results in the absence of mutant protein in septal myectomy and transplant tissue suggesting this duplication may destabilize the protein and lead to haploinsufficiency. In summary, c.3742_3759dup18 in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000463609 SCV000546482 pathogenic Hypertrophic cardiomyopathy 2020-01-06 criteria provided, single submitter clinical testing This sequence change inserts 18 nucleotides in exon 33 of the MYBPC3 mRNA (c.3742_3759dup). This leads to the insertion of 6 amino acid residues in the MYBPC3 protein (p.Gly1248_Cys1253dup) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with HCM in affected families (PMID: 20474083, 7493025, 23549607, 24510615, 27532257). ClinVar contains an entry for this variant (Variation ID: 8603). Experimental studies using model organisms suggest that this in-frame variant affects the expression and structural stability of the MYBPC3 protein (PMID: 25031304, 12202917). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620220 SCV000737356 pathogenic Cardiovascular phenotype 2019-03-25 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000030290 SCV000987509 pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Color RCV001181534 SCV001346706 likely pathogenic Cardiomyopathy 2020-01-27 criteria provided, single submitter clinical testing
OMIM RCV000009134 SCV000029351 pathogenic Familial hypertrophic cardiomyopathy 4 1995-12-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000030290 SCV000052957 pathogenic Primary familial hypertrophic cardiomyopathy 2014-10-02 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223778 SCV000280267 likely pathogenic not provided 2014-10-15 no assertion criteria provided clinical testing 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).

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