ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3190+5G>A (rs587782958)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620265 SCV000735650 pathogenic Cardiovascular phenotype 2016-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Blueprint Genetics RCV000143916 SCV000188790 pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626633 SCV000747334 pathogenic Heart block; Hypertrophic cardiomyopathy; Tachycardia; Asymmetric septal hypertrophy; Dyspnea; Ventricular extrasystoles; Noncompaction cardiomyopathy 2017-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762845 SCV000893205 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000158222 SCV000208157 pathogenic not provided 2017-02-09 criteria provided, single submitter clinical testing The c.3190+5 G>A pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Rodriguez-Garcia et al., 2010; Zou et al., 2013). Rodriguez-Garcia et al. (2010) identified c.3190+5 G>A in an individual with HCM with a family history of sudden death, and also in the proband's two daughters, one of which was affected with HCM. The c.3190+5 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, this pathogenic variant destroys the splice donor site in intron 29 and is expected to result in skipping of exon 29, which results in a truncated protein (Rodriguez-Garcia et al., 2010; Crehalet et al., 2012).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000625072 SCV000743676 pathogenic Familial hypertrophic cardiomyopathy 4 2017-07-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000143916 SCV000919809 pathogenic Primary familial hypertrophic cardiomyopathy 2018-12-03 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.3190+5G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to exon 29 skipping (Crehalet_2012). The variant allele was found at a frequency of 1.7e-05 in 236140 control chromosomes. c.3190+5G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Crehalet_2012, Rodrguez-Garca_2010, Zou_2013). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000227910 SCV000284240 pathogenic Hypertrophic cardiomyopathy 2018-11-06 criteria provided, single submitter clinical testing This sequence change falls in intron 29 of the MYBPC3 mRNA. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. This variant is present in population databases (rs587782958, ExAC <0.01%). This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (HCM) from the same family (PMID: 20433692) and in two other unrelated individuals also affected with HCM (PMID: 20800588, http://dx.doi.org/10.4081/cardiogenetics.2012.e6). ClinVar contains an entry for this variant (Variation ID: 155808). Experimental studies have shown that this intronic sequence change disrupts mRNA splicing causing exon 29 skipping that results in a truncated protein, and therefore loss-of-function, probably inducing transcript degradation via nonsense mediated decay (http://dx.doi.org/10.4081/cardiogenetics.2012.e6). Loss-of-function variants 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 RCV000227910 SCV000203979 pathogenic Hypertrophic cardiomyopathy 2015-02-25 criteria provided, single submitter clinical testing The c.3190+5G>A variant in MYBPC3 has been reported in 6 individuals with hypert rophic cardiomyopathy (HCM) as well as in 1 affected relative (Rodriguez-Garcia 2010, Crehalet 2012, ClinVar: Variation ID 155808, submission accession: SCV0001 88790.3). This variant has also been identified by our laboratory in 4 Caucasian adults with HCM and segregated with disease in 6 affected relatives from 2 fami lies. In addition, the c.3190+5G>A variant has been identified in 1/15392 Africa n chromosomes by gnomAD (http://gnomad.broadinstitute.org). The c.3190+5G>A vari ant is located in the 5' splice region. Splice variants are prevalent in individ uals with HCM and the c.3190+5G>A variant has been shown to result in skipping o f exon 29 (Crehalet 2012), which is predicted to result in a truncated or absent protein. Splice variants and other truncating variants in MYBPC3 are establishe d as pathogenic for HCM. In summary, the c.3190+5G>A variant meets criteria to b e classified as pathogenic for HCM in an autosomal dominant manner based upon pr esence in multiple affected individuals, segregation studies, very low frequency in controls and impact to the protein. ACMG/AMP Criteria applied: PP1_Strong, P M2, PVS1 PS4_Moderate.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158222 SCV000280257 likely pathogenic not provided 2012-02-17 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS29+5 G>A Given the type of variant, the case data, the in vitro data, and the absence in general population samples we consider this variant likely disease causing. The variant has been seen in at least 10 unrelated cases of HCM. There is weak segregation data from two families. Rodriguez-Garcia et al (2010) reported the variant in one of 20 individuals from their Spanish cohort. It segregated with disease in two affected first degree relatives. In an abstract from the 2005 HUGO meeting, an Australian group reported that they observed the variant in an individual with HCM in a cohort of 150 individuals that had DHLPC-based analysis of MYH7 and MYBPC3 (Yu et al 2005). Ancestry was not reported. Crehalet et al (2012) observed the variant in a patient with HCM from their French cohort of 280 HCM patients. Rodriguez-Garcia et al (2010) note that bionformatics analysis predicted an impact on splicing (programs used were reported as SSF, ASSP, NetGene2, HSF). The nucleotide at the +5 position of the consensus splice junction sequence. Crehalet et al (2012) note that 3 of 5 splicing algorithms they used predicted aberrant splicing. They assessed impact on splicing using a mini-gene assay and found that exon 29 was completely skipped and the resulting transcript include a premature stop codon and would likely be subject to nonsense-mediated decay. Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). Many MYBPC3 splice variants have been reported in association with HCM including IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 5th, 2014). There are no variants at the splice donor site in intron 29 listed in that dataset. It is listed in the 1000 genomes browser, but this appears to point to the HGMD listing and an online database that appears to be connected to Yu et al. The variant was not observed in the following published control samples: 200 controls (Rodriguez-Garcia et al 2010).

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