ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1458-6G>A (rs375347534)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000157325 SCV000207060 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-01-07 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770369 SCV000901810 uncertain significance Cardiomyopathy 2017-09-29 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000230101 SCV000886821 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000600435 SCV000744853 pathogenic Familial hypertrophic cardiomyopathy 4 2017-05-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000600435 SCV000733051 likely pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
GeneDx RCV000766336 SCV000208024 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing The c.1458-6 G>A variant of uncertain significance in the MYBPC3 gene has been published previously in association with HCM (Havndrup et al., 2003; Andersen et al., 2004). Havndrup et al. (2003) reported the c.1458-6 G>A variant in two affected individuals from one family with HCM. However, both of these individuals also harbored a missense variant in the MYH7 gene and an additional affected relative harbored only the MYH7 missense variant. Therefore, the contribution of each variant to the clinical presentation in this family is unclear. The c.1458-6 G>A variant has also been identified, both independently and/or in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The c.1458-6 G>A variant is observed in 6/111,314 alleles from individuals of European (non-Finnish) ancestry and 2/30,684 alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). In silico analysis predicts the c.1458-6 G>A variant may create a cryptic splice acceptor site, which could lead to abnormal splicing and protein truncation or absence of protein from this allele due to nonsense-mediated mRNA decay. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Nevertheless, numerous other downstream splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000600435 SCV000743563 pathogenic Familial hypertrophic cardiomyopathy 4 2016-04-04 criteria provided, single submitter clinical testing
Invitae RCV000230101 SCV000284212 uncertain significance Hypertrophic cardiomyopathy 2018-10-17 criteria provided, single submitter clinical testing This sequence change falls in intron 16 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. This variant is present in population databases (rs375347534, ExAC 0.01%). This variant has been reported in individuals from one family affected with hypertrophic cardiomyopathy (HCM) that also carried a likely pathogenic variant in MYH7 (p.Arg694Cys) which was suggested to be the primary cause of disease (PMID: 12566107, 15114369). In addition, this variant co-occurred with a MYBPC3 pathogenic variant in one individual tested at a clinical laboratory (ClinVar ID: 42533), which suggests that the c.1458-6G>A substitution in MYBPC3 was not the primary cause of disease in that individual. This variant is also known in the literature as g10899G>A and IVS16-6G>A. ClinVar contains an entry for this variant (Variation ID: 42533). Experimental studies have shown that this intronic change affects MYBPC3 mRNA splicing (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035399 SCV000059047 uncertain significance not specified 2011-03-24 criteria provided, single submitter clinical testing The 1458-6G>A variant has been reported in 1 family with HCM that also carried a second variant in MYH7 (Arg694Cys) that was felt to be the primary cause of dis ease (Andersen 2004). Please note, the 1458-6G>A variant was listed as g10899G> A and IVS16-6G>A in this paper. In addition, this variant was identified in a to tal of 3 individuals with HCM tested by our laboratory, one of whom carried a se cond pathogenic MYBPC3 variant (1224-2A>G). The 1458-6G>A variant is located in the 3' splice region but does not affect the highly conserved -1 and -2 position s. However, positions -3 and -5 to -12 are part of the splicing consensus sequen ce and variants involving these positions sometimes affect splicing. It should b e noted that research on a similar variant in intron 16 of this gene (1458-7C>T) has been demonstrated to result in an altered splice form (personal communicati on from Dr. Jon Seidman). Although this data suggests that the 1458-6G>A may cau se or modify disease, additional information is required to fully assess the imp act of this variant. Therefore, the clinical significance of this variant cannot be determined at this time.

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