ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2308+1G>A (rs112738974)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000473746 SCV000059126 pathogenic Hypertrophic cardiomyopathy 2011-08-11 criteria provided, single submitter clinical testing The 2308+1A>G variant has ben reported in a large number of individuals with HCM and was absent from at least 1000 control chromosomes tested (Oliva-Sandoval 20 10, Richard 2003, Carrier 1997, Ehlermann 2008, Gandjbakch 2010). This variant is predicted to cause abnormal splicing because the nucleotide substitution occ urs in the highly conserved splice consensus sequence. Abnormal splicing can le ad to loss of function of the affected allele, which is an established disease m echanism for the MYBPC3 HCM patients. In summary, this variant meets our criteri a for pathogenicity (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls and prevalence of loss of function variants in HCM pat ients.
GeneDx RCV000158147 SCV000208082 pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing The c.2308+1 G>A pathogenic variant (also denoted IVS23+1 G>A due to a difference in nomenclature) has been reported in several unrelated individuals with HCM and has been shown to segregate with disease in multiple families (Richard et al., 2003; Ehlermann et al., 2008; Oliva- Sandoval et al, 2010; Gandjbakhch et al., 2010). Oliva-Sandoval et al. (2010) identified the variant in 18/154 unrelated Spanish individuals diagnosed with HCM and in all relatives of these individuals (n= 40) also diagnosed with HCM. A history of sudden death was reported in 12/18 families, and those who harbored this variant were diagnosed at younger ages compared to individuals with HCM in this cohort who did not harbor the variant (Oliva-Sandoval et al, 2010). This variant destroys the canonical splice donor site in intron 23 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.2308+1 G>A variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000473746 SCV000546406 pathogenic Hypertrophic cardiomyopathy 2019-03-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 23 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 a family with hypertrophic cardiomyopathy (PMID: 9048664) and in many other unrelated individuals with hypertrophic cardiomyopathy (PMID: 12707239, 18957093, 21088121). This variant is also known as IVS23+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 42610). 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.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009140 SCV000744843 pathogenic Familial hypertrophic cardiomyopathy 4 2017-05-31 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000473746 SCV000886759 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256692 SCV001433091 pathogenic Familial hypertrophic cardiomyopathy 1 2020-04-21 criteria provided, single submitter clinical testing
OMIM RCV000009140 SCV000029357 pathogenic Familial hypertrophic cardiomyopathy 4 1997-03-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000035478 SCV000190380 pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000035478 SCV000207062 pathogenic Primary familial hypertrophic cardiomyopathy 2014-11-27 no assertion criteria provided clinical testing

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