ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1000G>A (p.Glu334Lys) (rs573916965)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777780 SCV000913755 uncertain significance Cardiomyopathy 2018-10-12 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the MyBP-C motif, myosin (S2) binding region of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may destabilize the protein through ubiquitin-proteasome system, modify the levels of channel proteins and induce apoptosis (PMID: 18929575, 21939669, 23740383). However, clinical relevance of these observations is unclear. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy, mostly of East Asian ancestry (PMID: 18929575, 21511876, 23283745, 23711808, 25132132, 26090888, 26163040). This variant has also been identified in 66/275480 chromosomes (65 /18810 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
GeneDx RCV000656915 SCV000208260 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing The E334K variant of uncertain significance in the MYBPC3 gene has been reported multiple times in association with HCM (Anan et al., 2007; Bahrudin et al., 2008; Olivotto et al., 2008; Zou et al., 2013; Wang et al., 2014). Both Olivotto et al. (2008) and Zou et al. (2013) identified a patient with HCM who harbored E334K in addition to another missense variant in the MYBPC3 gene. More recently, Wu et al. (2015) reported E334K in a 45 year-old Chinese individual clinically diagnosed with sporadic restrictive cardiomyopathy (RCM). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members.E334K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Functional studies conducted by Bahrudin et al. (2008) demonstrated that E334K causes ubiquitin-proteasome system impairment by decreasing the level of proteasome and increasing apoptosis in mutant cells. Nevertheless, E334K was observed in 65/18,810 (0.35%) alleles from individuals of East Asian ancestry in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant in this population. Further supporting this claim is that the majority of individuals tested at GeneDx harboring the E334K variant have been of Asian ancestry.
Illumina Clinical Services Laboratory,Illumina RCV000778105 SCV000372374 pathogenic Familial hypertrophic cardiomyopathy 4 2017-04-27 criteria provided, single submitter clinical testing The MYBPC3 c.1000G>A (p.Glu334Lys) missense variant has been reported in at least 10 studies in which it is found in a heterozygous state in at least 11 patients with hypertrophic cardiomyopathy (Anan et al. 2007; Bahrudin et al. 2008; Olivotto et al. 2008; Gruner et al. 2011; Liu et al. 2013; Zou et al. 2013; Liu et al. 2015; Jang et al. 2015). The p.Glu334Lys variant was absent from 700 controls but is reported at a frequency of 0.00453 in the East Asian population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated that variant MYBPC3 had reduced expression and was less stable than wild type (Bahrudin et al. 2008). In vivo functional studies in mouse epitrochlearis muscle showed that variant MYBPC3 had reduced and diffuse sarcomere localization compared to wild type (Gurnett et al. 2010). Based on the evidence, the p.Glu334Lys variant is classified as pathogenic for hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000349011 SCV000372375 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000405438 SCV000372376 benign Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000294264 SCV000546437 uncertain significance Hypertrophic cardiomyopathy 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 334 of the MYBPC3 protein (p.Glu334Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs573916965, ExAC 0.5%). This variant has been reported in the literature in many individuals affected with hypertrophic cardiomyopathy (PMID: 17560888, 18533079, 18929575, 21511876, 23283745, 23711808, 25132132, 26090888, 22455086). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 177902). Experimental studies have shown that this missense change impairs ubiquitination and increases apoptosis in transfected cells (PMID: 18929575, 21939669, 23740383). The clinical implication of this observation is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154555 SCV000204228 uncertain significance not specified 2019-02-28 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845545 SCV000987663 likely pathogenic Left ventricular noncompaction criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000154555 SCV000280203 uncertain significance not specified 2014-01-07 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.Glu334Lys Based on the data reviewed below we would typically consider a variant like this to be likely disease causing. However, we are concerned about the fact that nearly all of the reported cases are Japanese and we have very few Japanese controls. Given that we are considering it a variant of uncertain significance, likely disease causing and recommending further segregation analysis and ideally waiting for more Japanese control data. The variant has been seen in at least 4 unrelated cases of cardiomyopathy. Anan et al (2007) reported the variant in one Japanese patient with HCM. Bahrudin et al (2008) observed the variant in three unrelated Japanese patients (which seem to not overlap with the report by Anan et al). Of note, given our patient's phenotype, this patient had "giant negative T-waves". These patients were reported as part of their HCM cohort, however, the authors noted that patients with this variant had systolic dysfunction (35%, 44%, 49%) and dilation (66, 50, 59). All three had left ventricular hypertrophy with IVS thicknesses of 16, 17, and 14 mm. Unfortunately only minimal clinical data is available and it is not clear if these patients first presented with classical HCM. Notably, Bahrudin et al observed the variant in 3 of 30 patients with HCM studied, which is unusually high prevalence for one variant, possibly suggesting that the variant is a common one in the Japanese population in general. They did not comment whether the patients had a shared haplotype. Gruner et al (2011) observed the variant in a patient with apical HCM from their cohort in Toronto, ancestry was not listed. In silico analysis with PolyPhen-2 predicts the variant to be benign while mutation taster predicts the variant to be disease causing. The glutamate at codon 334 is completely conserved across species, and neighboring amino acids are highly conserved. Another variant has been reported in association with disease at a nearby codon (p.Ile336Val). I could not find any other variants assocaited with disease at codon 334. Bahrudin et al (2008) reported that the myosin-binding protein was more quickly degraded by the ubiquitin-proteasome system. In total the variant has not been seen in at least ~6600 published controls and publicly available population datasets, though few of these match the ancestry of the published cases. There is no variation at codon 334 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6400 Caucasian and African American individuals (as of 1/17/2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/17/2013), this probably includes 200 individuals of various Asian ancestries, though it is hard to be sure. There is no variation at codon 334 listed in the NIEHS exome data set, which includes 24 Asian individuals (as of 27th Sept 2012). The variant was not observed in the following published control samples: Anan et al (2007) did not see the variant in 100 controls (ancestry not noted). Bahrudin et al (2008) did not see the variant in 100 controls (ancestry not noted).

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