ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1321G>A (p.Glu441Lys) (rs193922377)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035382 SCV000059030 uncertain significance not specified 2015-04-09 criteria provided, single submitter clinical testing The p.Glu441Lys variant in MYBPC3 has been observed in 10/62060 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922377) and has been reported in at least 9 individuals with HCM, 2 o f whom carried other pathogenic variants (Olivotto 2008, Marsiglia 2010, Millat 2010, Olivotto 2011, Coto 2012, Kassem 2013). Our laboratory has identified this variant in 2 individuals with HCM and 1 individual with biatrial enlargement wh o carried another pathogenic HCM variant. The individual carrying the additional pathogenic HCM variant appeared to have an earlier onset of disease and a more severe presentation relative to the other patients carrying the Glu441Lys varian t. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, the clinical sig nificance of the p.Glu441Lys variant is uncertain. The available data raise the possibility that it is independently disease causing but milder in isolation but additional data is needed to confirm its significance.
GeneDx RCV000656916 SCV000208011 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing The E441K variant of uncertain significance in the MYBPC3 gene has been reported multiple times in association with HCM (Olivotto et al., 2008; Di Donna et al., 2010; Marsiglia et al., 2010; Millat et al., 2010; Coto et al., 2012, Kassem et al., 2013; Liu et al., 2015). Olivotto et al. (2008) and Di Donna et al. (2010) both reported the E441K variant in one patient diagnosed with HCM who also carried another MYBPC3 pathogenic variant (E258K); however, due to lacking clinical information provided in Olivotto et al. (2008), it is unclear whether both publications reference the same individual. Millat et al. (2010) identified E441K in an individual with HCM who also harbored two other MYBPC3 variants on the same allele, as well as one MYH7 variant. Marsiglia et al. (2010) reported the E441K variant in isolation in one patient with moderate HCM and suggested this variant leads to a milder phenotype in the absence of other pathogenic variants. Additionally, Kassem et al. (2013) identified the E441K variant in four of 199 Egyptian HCM probands, and Coto et al. (2012) identified this variant in two of 150 Spanish HCM patients. The E441K variant has been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. Of note, internal segregation data obtained from two families identified E441K both in cis and trans, respectively, with a pathogenic MYBPC3 variant. The E441K variant was observed in 40/274868 (0.015%) alleles from individuals multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the E441K variant 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Molecular modeling studies suggest that E441K causes conformational changes in cardiac myosin binding protein-C and interferes with normal binding/unbinding of the N-terminal complex, C1-motif-C2; however, the changes induced by E441K are less pronounced than those associated with the MYBPC3 E258K pathogenic variant (Gajendrarao et al., 2015; Krishnamoorthy et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000545018 SCV000623524 uncertain significance Hypertrophic cardiomyopathy 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 441 of the MYBPC3 protein (p.Glu441Lys). 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 (rs193922377, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 23233322, 24093860, 26090888, 28420666, 22765922, 20624503, 20414521, 21835320). However, in some of these individuals pathogenic alleles were also identified in MYBPC3, which suggests that this c.1321G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 36601). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MYBPC3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618738 SCV000740239 uncertain significance Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Insufficient evidence
Mendelics RCV000603246 SCV001138305 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656916 SCV001148279 likely benign not provided 2018-09-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030279 SCV000052946 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000030279 SCV000190406 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000030279 SCV000207039 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-04-11 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035382 SCV000280210 uncertain significance not specified 2013-05-03 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.Glu441Lys We consider this a variant of uncertain significance. This variant has been seen in at least 7 presumably unrelated individuals with hypertrophic cardiomyopathy (HCM). I was unable to find any reports of this variant with dilated cardiomyopathy. Notably, all of the individuals with this variant had at least one other sarcomere variant. There is no segregation data available on this variant. Olivotto et al. (2008) reported p.Glu441Lys in one patient with HCM who also carried another MYBPC3 variant (p.Glu258Lys). No data regarding phase or severity of phenotype were reported. Millat et al. (2010) reported one individual with HCM who had three variants on one MYBPC3 allele (p.Glu441Lys, p.Gln76Ter, p.Gly279Ala) and also had an additional variant in MYH7 (p.Ile1927Phe). Unfortunately age of onset and severity were not reported. Marsiglia et al (2010) reported the variant in one individual with HCM in Brazil (article is in Portuguese, further details not available). p.Glu441Lys has also been observed in two other unrelated individuals with HCM tested at GeneDx. One individual had two MYBPC3 missense variants and one MYH7 missense variant, was diagnosed with HCM in childhood and required transplant. The other individual was diagnosed with HCM as a child and was a compound heterozygote for this variant and an MYBPC3 frameshift variant (both parents were unaffected). The Seidmans' research group report this variant online in an individual who presumably has HCM and is a compound heterozygote for this variant and p.Glu258Lys (Merk et al 2005, http://genepath.med.harvard.edu/~seidman/cg3/muts/MYBPC3_Glu441Lys.html) This is a semi conservative amino acid substitution of a polar negative Glutamic Acid with a polar positive Lysine. Glutamic Acid is highly conserved at position 441. This variant was not identified in 150 presumably healthy individuals by Olivotto et al (2008). Millat et al (2010) did not do population studies. NHLBI Exome Sequence Variant Database reports p.Glu441Lys in 2 out of 4243 European American individuals and 3 out of 2138 African American individuals. 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. Based on these data, we consider this variant to be of uncertain significance. This classification is based on the fact that it has primarily (possibly only) been seen in combination with other variants and it has not yet been demonstrated that this variant can cause cardiomyopathy on its own or that it contributes in a significant way when in combination with other variants.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656154 SCV000678348 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000603246 SCV000733054 uncertain significance Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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