ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1624G>C (p.Glu542Gln) (rs121909374)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201915 SCV000256661 pathogenic Familial hypertrophic cardiomyopathy 1 2015-06-30 criteria provided, single submitter research The MYBPC3 Glu542Gln has previously been reported in multiple unrelated HCM cases (see references). Studies have shown the variant to co-segregate with disease in familial HCM (Carrier et al, 1997; Saltzman et al, 2010) however, we note that Saltzman et al. (2010) also identified an additional known disease-causing variant (MYBPC3 Arg502Trp). We have identified this variant in 4 unrelated HCM probands in our cohort. Familial segregation was performed where possible and was found to segregate with disease in a total of 6 individuals (2 in one family, 4 in another family). MYBPC3 Glu542Gln is a rare variant with a minor allele frequency of 0.00002485 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The variant affects the last nucleotide of exon 17 and has been shown to impact splicing (exon 17 skip) and result in an aberrant transcript (Carrier et al, 1997; Crehalet et al, 2012). In silico tools (SIFT, PolyPhen2, MutationTaster) are supportive of this variant having a disease-causing effect. Furhermore, loss-of-function variants in MYBPC3 including splice variants, are an established mechanism of disease in HCM. Based on the observation of MYPBC3 Glu542Gln in multiple HCM patients in independent studies and our cohort, its rarity in the general population, and our familial segregation analyses, we classify this variant as "pathogenic".
Ambry Genetics RCV000247235 SCV000319843 pathogenic Cardiovascular phenotype 2017-08-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Other data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Functionally-validated splicing mutation
Blueprint Genetics RCV000035424 SCV000207041 pathogenic Primary familial hypertrophic cardiomyopathy 2014-10-27 no assertion criteria provided clinical testing
Blueprint Genetics RCV000158104 SCV000927598 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000035424 SCV000190378 pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000009139 SCV000494449 pathogenic Familial hypertrophic cardiomyopathy 4 2016-03-30 criteria provided, single submitter clinical testing
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000505586 SCV000599924 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2014-06-09 no assertion criteria provided research This variant has been previously reported as disease-causing. It was an incidental finding in our study, in a 3-year-old male with Wilms tumor.
GeneDx RCV000158104 SCV000208039 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing The c.1624 G>C (E542Q) pathogenic variant in the MYBPC3 gene has been published in several individuals with HCM and reported to segregate with disease in multiple affected individuals from unrelated families (Carrier et al., 1997; Richard et al., 2003; Van Driest et al., 2004; Garcia-Castro et al., 2009; Rodriguez-Garcia et al., 2010; Marsiglia et al., 2013; Davis et al., 2015; Rubattu et al., 2016; Walsh et al., 2017; SCV000059072.5, Landrum et al., 2016). It has also been observed in multiple individuals with HCM referred for genetic testing at GeneDx. Additionally, this variant has been reported in individuals with severe disease who harbored a second variant in the MYBPC3 gene (Ingles et al., 2005; Saltzman et al., 2010; Bales et al., 2016; Rafael et al., 2017). Moreover, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).At the mRNA level, c.1624 G>C occurs at the last nucleotide of exon 17 and is predicted to damage the natural splice donor site in intron 17 and lead to abnormal gene splicing. Multiple functional studies, including transcript analyses of patient lymphocytes or heart tissue as well as in vitro splice assays, demonstrate that this variant causes exon 17 skipping while normally spliced transcripts harboring the missense change are also expressed (Carrier et al., 1997; Marston et al., 2012; Helms et al., 2014; Ito et al., 2017). Furthermore, at the protein level, E542Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, a study of fetal rat cardiomyocytes suggests that E542Q may have a dominant negative effect on sarcomere function (Flavigny et al., 1999).In summary, c.1624 G>C (E542Q) in the MYBPC3 gene is interpreted as a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000009139 SCV000584103 pathogenic Familial hypertrophic cardiomyopathy 4 2015-12-10 criteria provided, single submitter research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000009139 SCV000993585 pathogenic Familial hypertrophic cardiomyopathy 4 2018-12-10 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000247235 SCV000696317 pathogenic Cardiovascular phenotype 2016-09-19 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.1624G>C (p.Glu542Gln) variant involves the alteration of the conserved last nucleotide of exon 17. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict the complete loss or reduction in cannonical splice donor site. Functional studies have confirmed that this variant causes the skipping of exon 17 and truncated protein product (Carrier_1997, Marston_2012, Helms_2014). This variant was found in 2/81374 control chromosomes at a frequency of 0.0000246, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The variant has been reported in numerous affected individuals in the literature, including family members in which the variant segregated with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000199033 SCV000253809 pathogenic Hypertrophic cardiomyopathy 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 542 of the MYBPC3 protein (p.Glu542Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. It also falls at the last nucleotide of exon 17 of the MYBPC3 mRNA. This variant is present in population databases (rs121909374, ExAC 0.01%). This sequence change has been reported to segregate with disease (PMID: 9048664, 20433692). It has also been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 9631872, 25031304, 15519027, 18533079, 16199542, 27532257). This variant is also known as c.1679G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 8608). Experimental studies using cardiac tissue and lymphocytes derived from HCM patients have shown that this sequence change causes skipping of exon 17 introducing a premature stop codon, which results in the generation of a truncated protein product (PMID: 22057632, 25031304, 9048664) and lower incorporation into the sarcomere compared to wild-type (PMID: 10610770). Truncating variants in MYBPC3 are known to be pathogenic (PMID: 19574547). In summary, this sequence change has been reported in affected individuals and shown to segregate with disease. In addition, it affects protein expression and leads to a truncated protein. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000199033 SCV000059072 pathogenic Hypertrophic cardiomyopathy 2016-07-21 criteria provided, single submitter clinical testing The p.Glu542Gln variant in MYBPC3 has been identified in greater than 50 individ uals with HCM and segregated with disease in greater than 10 affected individual s from multiple families (Carrier 1997, Page 2012, Fokstuen 2011, Rodriguez-Garc ia 2010, Barriales-Villa 2010, Garcia-Castro 2009, Olivotto 2008, Girolami 2006, Ingles 2005, Van Driest 2004, Richard 2003, Crehalet 2012, Walsh 2017, LMM data ). This variant has also been identified in 4/117922 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 121909374). This variant is located in the last three bases of the exon, which i s part of the 5? splice region. Computational tools suggest an impact to splicin g, which was confirmed by in vitro studies (Carrier 1997, Crehalet 2012, Ito 201 7). Pathogenic splice variants in the MYBPC3 gene are common in HCM patients. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based on prevalence among affected individuals, seg regation studies, and observed impact on splicing. ACMG/AMP Criteria applied: PS 4; PP1_Strong; PVS1_Strong; PM2.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627130 SCV000747943 pathogenic Familial dilated cardiomyopathy 2017-04-24 criteria provided, single submitter clinical testing
OMIM RCV000009139 SCV000029356 pathogenic Familial hypertrophic cardiomyopathy 4 1997-03-01 no assertion criteria provided literature only
Phosphorus, Inc. RCV000009139 SCV000679775 pathogenic Familial hypertrophic cardiomyopathy 4 2017-08-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158104 SCV000280219 likely pathogenic not provided 2013-11-04 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 p.Glu542Gln Based on the data reviewed below we classify this variant as likely disease causing. This variant has been observed in at least 13 individuals with HCM. It has been published in association with Hypertrophic Cardiomyopathy (HCM). We have also observed this variant in two other patients with HCM. Carrier et al (1997) reported the variant in two unrelated families with HCM with the variant segregating with HCM in 3 individuals in each family (same families reported in Charron et al 1998). Richard et al (2003) reported the variant in two unrelated individuals with HCM. Van Driest et al (2004) reported the variant in one case of HCM (likely reported again in Olivotto et al 2011). Ingles et al (2005) reported the variant in a patient with HCM who also had another variant in MYBPC3 (p.Ala851Val). Fokstuen et al (2011) reported the variant in an individual with HCM. Page et al (2012) reported one individual with HCM with this variant in their British cohort. Saltzman et al (2010) reported the variant in two unrelated individuals with HCM who also carried p.Arg502Trp in MYBPC3 from their American cohort. This is the most common HCM disease-causing variant in the US and we consider it very likely disease causing. These patients had more severe disease than the patients in their series with just p.Arg502Trp. Crehalet et al (2012) observed the variant in an individual with HCM from their French cohort (this appears to be a distinct case from the one previously reported by Carrier and Charron). The variant affects the last nucleotide of the exon, changing it from the consensus G to a C. Carrier et al (1997) examined cDNA and reported that this variant leads to skipping of exon 17 and introduction of a premature stop codon. In a myectomy sample from a patient with this variant Vydyanath et al (2012) observed skipping of exon 17 and a 28% deficiency of the myosin binding protein. Crehalet et al (2012) observed multiple aberrant splicing products in their in vitro experiments. The variant has been seen in 1 of ~ 6957 published controls and individuals from publicly available general population datasets. This variant has not been seen in a total of 650 published controls, including 200 individuals examined by van Driest et al (2004), 100 control individuals reported by Richard et al (2003), 150 control individuals reported by Ingles et al (2005) and 200 control individuals reported by Carrier et al (1997). The variant is listed in dbSNP (rs121909374) as variant associated with a Mendelian phenotype in OMIM but with no population frequency data (as of January 2nd, 2013). It is listed in the 1000 genomes data set, but only in reference to the dbSNP listing (as of January 2nd, 2013). The variant was reported online in 0 of 4208 Caucasian individuals and 1 of 2099 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of April 4th, 2013). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other variants with strong evidence for pathogenicity have been observed at this low frequency in this dataset.

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