ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3811C>T (p.Arg1271Ter) (rs397516042)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621330 SCV000740206 pathogenic Cardiovascular phenotype 2017-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000208264 SCV000264044 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-02-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515345 SCV000611211 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000158271 SCV000208206 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing p.Arg1271Stop (CGA>TGA): c.3811 C>T in exon 33 of the MYBPC3 gene (NM_000256.3). The R1271X mutation in the MYBPC3 gene has been reported previously in association with HCM (Olivotto I et al., 2008; Marston S et al., 2009) and was absent from 300 ethnically matched control chromosomes (Olivotto et al., 2008). The R1271X mutation is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein. Numerous other truncating mutations in the MYBPC3 gene have been reported in association with HCM. In addition, R1271X was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, R1271X in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV000475268 SCV000546415 likely pathogenic Hypertrophic cardiomyopathy 2018-11-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MYBPC3 gene (p.Arg1271*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 4 amino acids of the MYBPC3 protein. This variant is present in population databases (rs397516042, ExAC 0.009%). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 18533079, 19574547, 23396983, 27532257, Invitae) and in one individual affected with dilated cardiomyopathy (DCM) who also carried a different pathogenic variant in MYBPC3 (PMID: 19996403). ClinVar contains an entry for this variant (Variation ID: 42744). Experimental studies have shown that this nonsense change results in undetectable truncated MYBPC3 protein, but with modest reduction of MYBPC3 mRNA by RT-PCR (PMID: 19574547). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000475268 SCV000059270 pathogenic Hypertrophic cardiomyopathy 2014-11-12 criteria provided, single submitter clinical testing The p.Arg1271X variant in MYBPC3 gene has been previously reported in 3 individu als with HCM (Olivotto 2008, Marston 2009, Lopes 2013) and was identified by our laboratory in 1 individual with DCM and in 2 individuals with HCM (LMM unpublis hed data). It was absent from large population studies ( .edu/EVS/). This nonsense variant leads to a premature termination codon at posi tion 1271, which is predicted to lead to a truncated or absent protein and funct ional evidence supports a loss-of-function effect (Marston 2009). Heterozygous l oss-of-function of the MYBPC3 gene is an established disease mechanism in HCM. I n summary, this variant meets our criteria to be classified as pathogenic for HC M in an autosomal dominant manner ( LMM) based upon the predicted impact of the variant, functional evidence, and ab sence from controls.

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