ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3628-41_3628-17del (rs36212066)

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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 RCV000158391 SCV000203933 likely benign not specified 2020-08-14 criteria provided, single submitter clinical testing The c.3628-41_3628-17del variant in MYBPC3 has been identified in 3.2% (981/30592) of South Asian chromosomes, including 19 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). This variant has been previously considered to be a common low-penetrance variant associated with milder, late-onset HCM in the heterozygote state, or early-onset disease in an autosomal recessive manner (Dhandapany 2009 PMID: 19151713, Waldmuller 2003 PMID: 12788380, Tanjore 2008 PMID: 18273486, Bashyam 2012 PMID: 21959974). A recent report has shown that this variant is not directly associated to cardiomyopathy but rather is in tight linkage disequilibrium with a rare intronic pathogenic MYBPC3 variant (c.1224-52G>A) that is reported to be one of the most frequent pathogenic variants associated to HCM in both Europeans and South Asians (Harper 2020 PMID: 32163302). Thus, the risk previously attributed to this variant can be explained by the intronic c.1224-52G>A variant. In summary, this variant is classified as likely benign. ACMG/AMP Criteria applied: BS1, BP2.
GeneDx RCV000158391 SCV000208326 uncertain significance not specified 2017-03-08 criteria provided, single submitter clinical testing The c.3628-41_3628-17del25 variant in the MYBPC3 gene has been reported in association with HCM (Waldmulleret al., 2003; Tanjore et al., 2008; Dhandapany et al., 2009). Waldmuller et al. (2003) describe two families of SouthAsian ancestry with hypertrophic cardiomyopathy; in one family the proband also harbored a deletion in MYH7 andrelatives with the c.3628-41_3628-17del25 variant alone were either mildly affected or unaffected. In the second family2/4 relatives with this variant were affected. Using exon trapping" in transfected COS1 cells and neonatal ratcardiomyocytes, Waldmuller et al. (2003) demonstrated that, in the presence of the deletion, wild type protein ispresent, though reduced; some residual normal splicing occurs. Tanjore et al. (2008) describe thec.3628-41_3628-17del25 variant in two probands with HCM and in 3/60 control samples. The first proband hadobstructive HCM and a mildly affected daughter. The second proband had obstructive HCM and two affected sons,though only one son had the variant. Dhandypany et al. (2009) analyzed RNA and protein from endomyocardialbiopsy in two young probands and noted both normal transcript and abnormal transcript with associated skipping ofexon 33, though no altered protein was detected in the biopsy samples. Functional studies by Waldmuller et al.(2003) and Dhandapany et al. (2009) demonstrate this variant removes the splice branch point sequence in intron 32,predisposes to exon skipping and contributes to abnormal sarcomeric architecture in rat cardiomyocytes.This variant has been reported in ClinVar as likely pathogenic by another clinical laboratory (ClinVarSCV000203933.3; Landrum et al., 2016). The c.3628-41_3628-17del25 variant is more common in individuals ofSouth Asian ancestry but is statistically more prevalent in affected individuals and homozygotes have severe,early-onset disease (Tanjore et al., 2009; Dhandapany et al., 2008; Simonson et al., 2010). Furthermore, this varianthas been seen in multiple individuals who had DNA-based testing for cardiomyopathy at GeneDx, although severalhad a second pathogenic allele identified. Additionally, the 1000 Genomes Project observed thec.3628-41_3628-17del25 variant in approximately 3% (32/978 alleles) in individuals of South Asian ancestry,indicating it may be a common variant/risk allele in this population. Therefore, based on the currently available information, it is unclear whether this variant is sufficient to cause disease when no other pathogenic variant is present. Current evidence suggests that this deletion may either be associated with a milder presentation with onset at a later age, or it may represent a modifier allele which may act in concert with other genetic or environmental factors. It also cannot be ruled out that this is a benign variant in South Asian populations. "
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000495611 SCV000579489 likely pathogenic Left ventricular noncompaction 10 2017-06-22 criteria provided, single submitter clinical testing
Invitae RCV000527487 SCV000623601 pathogenic Hypertrophic cardiomyopathy 2020-10-20 criteria provided, single submitter clinical testing This 25-base pair deletion falls in intron 32 of the MYBPC3 mRNA. It does not directly change the encoded amino acid sequence of the MYBPC3 protein, but it does affect the splicing branch point of the intron. (PMID: 12788380) This intronic sequence change is clearly defined as a hypertrophic cardiomyopathy causative allele (PMID: 20298698). It is a founder mutation in the South Asian population, and is found at a frequency of 3% (PMID: 24327208). A large scale association study found an approximately 7-fold increased risk for heart failure in carriers of this allele (PMID: 19151713). In addition, a study of 28 families containing a total of 120 individual carriers of this sequence change observed that more than 90% of the oldest members of each family were symptomatic even though most young and middle-aged individuals were either asymptomatic or had mild hypertrophy (PMID: 19151713). ClinVar contains an entry for this variant (Variation ID: 177677). Experimental studies have shown that this intronic change leads to skipping of exon 33 and a shorter protein product. (PMID: 12788380, 19151713). This is a well known founder mutation that has been shown to segregate with disease in multiple families and causes a deleterious effect on the MYBPC3 protein. For these reasons, this sequence change has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000527487 SCV000996366 uncertain significance Hypertrophic cardiomyopathy 2017-02-08 criteria provided, single submitter research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170948 SCV001333600 likely pathogenic Cardiomyopathy 2018-07-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170948 SCV001355390 likely benign Cardiomyopathy 2020-03-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000158391 SCV001448489 benign not specified 2021-03-12 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.3628-41_3628-17del25 (also reported as the MYBPC3 delta25 variant) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. In contrast, early publications demonstrated that the variant affects normal splicing leading to skipping of exon 33 and a loss of 62 amino acids that modified the C10 domain of the MYBPC3 protein (Waldmuller_2003, Dhandapany_2009). However, both residual normally spliced and deleted transcripts were reported in these studies, therefore the exact in-vivo consequence of this finding remains questionable in light of additional reports summarized below. The variant allele was found at a frequency of 0.004 in 250036 control chromosomes, predominantly at a frequency of 0.032 within the South Asian subpopulation in the gnomAD database, including 19 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 32 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3628-41_3628-17del25 has been reported in the literature predominantly in studies of South Asian individuals affected with Hypertrophic Cardiomyopathy (example, Waldmuller_2003, Tanjore_2008, Dhandapany_2009, Alfares_2015, Harper_2020). In a conservative ascertainment of families reported with this variant, we captured 7 transmissions of the variant allele and 5 transmissions of the reference allele to affected individuals (Waldmuller_2003, Tanjore_2008) suggestive of lack of segregation with disease. A recent study reported that the risk of HCM previously attributed to this 25-base pair deletion is explained by a linkage disequilibrium between this deletion and another deep intronic MYBPC3 variant, c.1224-52G>A which is causative of HCM (Harper_2020). Direct comparison of the proportion of heterozygous MYBPC3 delta25 variant carriers between the HCMR (17/134) and gnomAD (943/15 296) South Asian cohorts indicated a 2-fold enrichment within HCM cases (odds ratio [OR], 2.1 [95% CI, 1.2-3.4]; P=0.008). When HCMR probands with the MYBPC3 delta25/52 haplotype were excluded, no difference was observed (OR, 0.96 [95% CI, 0.40-1.95]; P=1.0). Therefore, these data do not allow any conclusion about the significance of c.3628-41_3628-17del25 in isolation. Multiple co-occurrences with other pathogenic variant(s) have been reported, example, PRKAG2 c.905G>A, p.Arg302Gln (Alfares_2015); MYBPC3 c.1224-52G>A; MYBPC3 c.2827C>T, p.Arg943*; MYBPC3 c.821+2T>C (Harper_2020), providing additional supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function in a mice model. The most pronounced variant effect results in an HCM phenotype in mice at 12 weeks of age and mislocalization of the mutant protein to the sarcomere resulting in its categorization as an at-risk allele for heart failure and adverse cardiovascular outcomes (Kuster_2019, Sadayappan_2020). However, in the context of our ascertainment, when objectively ascertained for the degree of reported contractile dysfunction and HCM in vivo attributed to this variant, the evidence as reported is not translatable to an in-vivo impact in humans (Kuster_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic, n=1; likely pathogenic, n=4, VUS, n=2; benign, n=1). Some submitters cite overlapping but not all the recently published evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant in isolation (MYBPC3 delta25) without the c.1224-52G>A variant, was re-classified as benign.
Clinical Genomics Program, Stanford Medicine RCV001254179 SCV001427228 likely pathogenic Familial hypertrophic cardiomyopathy 4 2020-03-12 no assertion criteria provided clinical testing The c.3628-41_3628-17del25 variant in the MYBPC3 gene has been previously reported in the heterozygous, compound heterozygous, or homozygous state in >30 unrelated individuals with cardiomyopathy (Alfares et al., 2015; Bashyam et al., 2012; Dhandapany et al., 2009; Waldmuller et al., 2003). The c.3628-41_3628-17del25 variant has also been identified in 981/30,592 South Asian chromosomes, including 19 homozygotes, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/), indicating it may be a common, reduced penetrance allele in this population. While the c.3628-41_3628-17del25 variant is relatively common in individuals of South Asian ancestry, case-control studies have found an associated risk with cardiomyopathy (Dhandapany et al., 2009). This variant is predicted to disrupt splicing and lead to skipping of exon 33, reducing the length of the protein (Dhandapany et al., 2009; Waldmuller et al., 2003). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.3628-41_3628- 17del25 variant as likely pathogenic with reduced penetrance for hypertrophic cardiomyopathy in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS4; PM4]

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