ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1235_1236del (p.Ile411_Phe412insTer) (rs397515894)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168331 SCV000059027 pathogenic Hypertrophic cardiomyopathy 2017-02-02 criteria provided, single submitter clinical testing The p.Phe412X variant has been reported in 3 individuals with HCM (Richard 2003, Van Driest 2004, LMM data). This variant was absent from large population studi es. This variant is a deletion of 2 bases resulting in a premature termination c odon at position 412, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of function of the MYBPC3 gene is an established disease me chanism in individuals with HCM. This variant has been reported in ClinVar (Vari ant ID: 42514). In summary, this variant meets our criteria to be classified as pathogenic based on the predicted impact of the variant.
GeneDx RCV000158344 SCV000208279 pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing The c.1235_1236delTT pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (also reported as del TT[10512-10513] and I411 fs/0) (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Berge et al., 2014; Kapplinger et al., 2014). Ehlermann et al. (2008) observed segregation of the c.1235_1236delTT variant with disease in a mother and son with HCM diagnosed at age 69 and 35, respectively. In addition, this variant is classified in ClinVar as a pathogenic variant by two other clinical laboratories (ClinVar SCV000059027.3; SCV000219019.2; Landrum et al., 2016). This variant was absent from more than 2,700 control alleles, collectively (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Kapplinger et al., 2014) and was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1235_1236delTT variant causes a shift in reading frame starting at codon Phenylalanine 412, changing this amino acid to a premature stop codon, denoted p.Phe412Stop. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014).
Invitae RCV000168331 SCV000219019 pathogenic Hypertrophic cardiomyopathy 2020-01-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe412*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and in a family affected with hypertrophic cardiomyopathy (PMID: 12707239, 18957093, 24111713, 24510615). ClinVar contains an entry for this variant (Variation ID: 42514). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587876 SCV000696311 pathogenic Cardiovascular phenotype 2016-05-04 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.1235_1236delTT (p.Phe412Terfs) variant is a frameshift mutation predicted to cause loss of normal protein function due to production of a truncated protein or by the absence of the protein product due to nonsense-mediated mRNA decay. Mutation taster predicts a damaging outcome for this variant. It was not found in 102952 control chromosomes while it was reported in several patients with HCM from the literature. In one family, the variant co-segregated with disease, indicating pathogenicity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu667fs), further supporting a deleterious outcome. In addition, clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.
Ambry Genetics RCV000587876 SCV000736945 pathogenic Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000158344 SCV000928149 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158344 SCV001249487 pathogenic not provided 2016-12-01 criteria provided, single submitter clinical testing

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