ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3490+1G>T (rs397516020)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158238 SCV000208173 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing The c.3490+1 G>T pathogenic variant (also reported as IVS32+1 G>T due to alternate nomenclature) in the MYBPC3 gene has been reported multiple times in association with cardiomyopathy (Zeller et al., 2006; Ehlermann et al., 2008; Hershberger et al., 2010). Zeller et al. (2006) initially reported that the c.3490+1 G>T variant co-segregated with a dilated cardiomyopathy (DCM) phenotype in one family with multiple affected relatives. Ehlermann et al. (2008) also found the c.3490+1 G>T variant co-segregated with a cardiomyopathy phenotype in one family, but noted that while affected relatives in older generations demonstrated a DCM phenotype, affected asymptomatic relatives in the youngest generation demonstrated an HCM phenotype. Additionally, the c.3490+1 G>T pathogenic variant in the MYBPC3 gene has been observed in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The c.3490+1 G>T variant destroys the canonical splice donor site of intron 31 of the MYBPC3 gene and is expected to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message, which is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other downstream splicing variants in the MYBPC3 gene, including one at the same nucleotide (c.3490+1 G>A), have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.3490+1 G>T pathogenic variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Illumina Clinical Services Laboratory,Illumina RCV000779061 SCV000915527 likely pathogenic MYBPC3-Related Disorders 2018-10-08 criteria provided, single submitter clinical testing The MYBPC3 c.3490+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.3490+1G>T variant has been reported in two studies in which it is found in a total of seven individuals, including six individuals with either dilated or hypertrophic cardiomyopathy from the same family (Zeller et al. 2006; Ehlermann et al. 2008). Another family member who experienced sudden death at the age of 32 was an obligate carrier of the variant based on family history and pedigree analysis. The variant was not found among 430 control individuals with normal systolic and diastolic function, nor was it found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database (Ehlermann et al. 2008). Based on the evidence including the potential impact of splice donor variants, the c.3490+1G>T variant is classified as likely pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000628980 SCV000749890 pathogenic Hypertrophic cardiomyopathy 2017-09-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 31 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 reported to segregate with hyperthrophic cardiomyopathy and dilated cardiomyopathy in a single family (PMID: 16715312). This variant is also known as intron 32+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 181008). 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.

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