ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3190+1G>A (rs111683277)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620737 SCV000740034 pathogenic Cardiovascular phenotype 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000158206 SCV000208141 pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing The c.3190+1 G>A pathogenic variant in the MYBPC3 gene has previously been reported inassociation with HCM (Wang et al., 2014; Alfares et al., 2015; Walsh et al., 2017). This variant hasalso been reported in one patient with idiopathic dilated cardiomyopathy (DCM) (Hershberger et al.,2010). This variant destroys the canonical splice donor site in intron 29 and ispredicted to cause abnormal gene splicing. The c.3190+1 G>A variant is predicted to lead to either anabnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal proteinproduct if the message is used for protein translation. Other downstream splice site variants in theMYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al.,2014). Additionally, a pathogenic splice site variant in the adjacent nucleotide of the MYBPC3 gene(c.3190+2 T>G) has also been reported in association with cardiomyopathy (Berge et al., 2014;Murphy et al., 2016). Furthermore, the c.3190+1 G>A variant is not observed in large populationcohorts (Lek et al., 2016).
GenomeConnect, ClinGen RCV000509397 SCV000607140 not provided Familial hypertrophic cardiomyopathy 4 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000628934 SCV000749842 pathogenic Hypertrophic cardiomyopathy 2018-12-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 29 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results 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 affected with hypertrophic cardiomyopathy and in an individual with dilated cardiomyopathy (PMID: 25132132, 20215591, 25611685, 27532257, Invitae). This variant is also known as splice site (29+1) in the literature. ClinVar contains an entry for this variant (Variation ID: 177837). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000628934 SCV000204141 pathogenic Hypertrophic cardiomyopathy 2018-03-19 criteria provided, single submitter clinical testing The c.3190+1G>A variant in MYBPC3 has been identified in at least 5 individuals with HCM (Wang 2015, LMM data) and in 1 individual with DCM (Hershberger 2010). This variant has also been identified in 1/9828 of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs111683277). This variant has also been reported in ClinVar (Variation ID: 177837). This variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. Splice site and other MYBPC3 variants resulting in a hetero zygous loss of function are strongly associated with HCM. In summary, this varia nt meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based upon predicted impact to the protein and presence in affected individuals. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Mode rate.

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