ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)

gnomAD frequency: 0.00004  dbSNP: rs397516074
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Total submissions: 31
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000205517 SCV000059319 pathogenic Hypertrophic cardiomyopathy 2019-05-14 criteria provided, single submitter clinical testing The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura 1998, Nanni 2003, Olivotto 2008, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42792) and has been identified in 4/124374 of European and in 2/23498 of African chromosomes by gnomAD (https://gnomad.broadinstitute.org/). The p.Glu258Lys variant is located in the last base of exon 6, which is part of the 5’ splice region. Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on case observations, segregation with disease, low frequency in the general population and observed impact on splicing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate.
Blueprint Genetics RCV000035668 SCV000188783 pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000158310 SCV000208245 pathogenic not provided 2019-10-28 criteria provided, single submitter clinical testing Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed as an Italian founder mutation (Girolami et al., 2006; Olivotto et al., 2008); Observed in 6/272910 global alleles in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of exon 6, which is part of the splice donor site; Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID 42792; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26671970, 30550750, 27532257, 23233322, 15114369, 29875424, 30165862, 28687478, 28679633, 30972196, 9562578, 19574547, 20359594, 18533079, 23283745, 22907696, 25031304, 23980194, 12951062, 26914223, 25971843, 21310275, 12707239, 15563892, 15519027, 23527136, 19590044, 15769446, 20031602, 22267749, 16858239, 28450932, 28790153, 29524613, 28916354, 12974739, 18957093, 27574918, 27267291, 27600940, 26869393, 25351510, 29447731, 30645170, 30446606, 31006259, 31737537, 31447099, 33673806, 33297573, 32686758)
Eurofins Ntd Llc (ga) RCV000158310 SCV000231501 pathogenic not provided 2015-04-03 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000161125 SCV000256170 likely pathogenic Hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Invitae RCV000205517 SCV000260690 pathogenic Hypertrophic cardiomyopathy 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein (p.Glu258Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397516074, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This variant is also known as E264K. ClinVar contains an entry for this variant (Variation ID: 42792). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6 and introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000247227 SCV000320235 pathogenic Cardiovascular phenotype 2022-03-30 criteria provided, single submitter clinical testing The c.772G>A pathogenic mutation (also known as p.E258K), located in coding exon 6 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. In one study, RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) with co-segregation and a suggested founder effect (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Bongini C. Am J Cardiol. 2016;117(7):1151-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Phosphorus, Inc. RCV000161125 SCV000679779 pathogenic Hypertrophic cardiomyopathy 4 2017-08-01 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000161125 SCV000693449 pathogenic Hypertrophic cardiomyopathy 4 2017-05-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000161125 SCV000744867 pathogenic Hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000035668 SCV000747994 pathogenic Primary familial hypertrophic cardiomyopathy 2016-12-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763244 SCV000893880 pathogenic Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2022-01-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035668 SCV000917820 pathogenic Primary familial hypertrophic cardiomyopathy 2017-12-12 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.772G>A (p.Glu258Lys) variant involves the alteration of a conserved nucleotide located just one nucleotide upstream from an exon-intron junction. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. This variant was found in 5/270526 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000205517 SCV000996340 pathogenic Hypertrophic cardiomyopathy 2017-03-21 criteria provided, single submitter research The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic".
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170208 SCV001332760 pathogenic Cardiomyopathy 2023-05-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001170208 SCV001359738 pathogenic Cardiomyopathy 2023-04-06 criteria provided, single submitter clinical testing This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 14563344, 12974739, 15114369, 15563892, 16858239, 1853307, 19808356, 19574547, 22267749, 23233322, 30645170, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000161125 SCV001367566 pathogenic Hypertrophic cardiomyopathy 4 2020-02-26 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,Ps4-MOD,PM2,PP1-M,PP3.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000161125 SCV001434957 pathogenic Hypertrophic cardiomyopathy 4 2018-10-02 criteria provided, single submitter clinical testing The c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, 23233322, 25031304). This variant has an extremely low frequency in large databases of genetic variation in the general population. mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304). Therefore, this c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene is classified as pathogenic.
Loeys Lab, Universiteit Antwerpen RCV000205517 SCV001572568 pathogenic Hypertrophic cardiomyopathy 2021-02-26 criteria provided, single submitter clinical testing This sequence change results in a missense variant in the MYBPC3 gene (p.(Glu258Lys)). This variant is present in population databases (GnomAD 6/272910). This variant has been reported in the literature in several unrelated individuals/families with HCM and cosegregated with disease (PP1) (PMID: 9562578; PMID: 12951062; PMID: 15519027; PMID: 12707239; PMID: 16858239). It was identified as a common variant among HCM patients in Italy (21% of the cases studied) (PMID: 18533079) (PS4). The variant affects a highly conserved position and alters the last base of exon 6, leading to skipping of exon 6. In cardiac tissue of HCM patients carrying the variant, no missense transcript was detected, indicating that the variant resulted in truncating mutant transcripts. These transcript however, did not result in any detectable truncated protein, since only wild-type protein was detected (PMID: 25031304). In neonatal rat cardiomyocytes it was shown that the truncated transcript underwent degradation by the ubiquitin-proteasome system ( PMID: 15769446) (PVS1). In murine a-engineered cardiac tissue the variant resulted in accelerated contractile kinetics, disruption of twitch force and absence of the interaction between cMyBP-C and myosin heavy chain sub-fragment 2 (PMID: 23980194) (PS3). In a knock-in mouse model homozygous mice showed left ventricular hypertrophy, reduced fractional shortening, and interstitial fibrosis; heterozygotes had no major phenotype.(PMID: 19590044). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.1828G>A, classified as variant of unknown significance). In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1; PS4;PS3).
CeGaT Center for Human Genetics Tuebingen RCV000158310 SCV001961282 pathogenic not provided 2023-08-01 criteria provided, single submitter clinical testing MYBPC3: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4
3billion RCV000161125 SCV002058951 pathogenic Hypertrophic cardiomyopathy 4 2022-01-03 criteria provided, single submitter clinical testing Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, PVS!_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000022, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic RCV000158310 SCV002103243 pathogenic not provided 2021-04-06 criteria provided, single submitter clinical testing PS3, PS4, PP1, PP3
Institute of Human Genetics, University of Leipzig Medical Center RCV000161125 SCV002587108 pathogenic Hypertrophic cardiomyopathy 4 2023-12-07 criteria provided, single submitter clinical testing Criteria applied: PS3,PS4,PM5
New York Genome Center RCV000763244 SCV003925302 pathogenic Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2022-09-21 criteria provided, single submitter clinical testing The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found to segregate in many additional affected family members [PMID:9562578]. This variant has been deposited in ClinVar [ClinVar ID: 42792] as Pathogenic/Likely Pathogenic. The c.772G>A variant is observed in 17 alleles (0.0021% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.772G>A variant in MYBPC3 is located in exon 6 of this 35-exon gene and is predicted to replace a moderately conserved glutamic acid with lysine amino acid at position 285 p.(Arg123Gln) in the phosphorylation domain of the c1 motif of the encoded protein [PMID:28658286,23233322, 15114369]. In addition, the c.772G>A variant is located one nucleotide away from the exon-intron junction of exon 6, therefore it may also affect the splicing. In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]. In silico predictions are inconclusive for p.(Arg123Gln) variant's effect [(CADD v1.6 = 51, REVEL = 0.616)]. Based on available evidence, this c.772G>A p.(Glu258Lys) variant identified in MYBPC3 is classified as Pathogenic.
Illumina Laboratory Services, Illumina RCV000161125 SCV004014736 pathogenic Hypertrophic cardiomyopathy 4 2023-05-02 criteria provided, single submitter clinical testing The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the available literature, this variant has been identified in a heterozygous state in greater than 50 unrelated individuals with hypertrophic cardiomyopathy (PMID: 18533079; PMID: 27532257). The highest frequency of this allele in the Genome Aggregation Database is 0.00004410 in the European (non-Finnish) population (version 3.1.2). This variant's nucleotide position coincides with a canonical splice donor site. Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194). A knock-in mouse carrying this variant has been developed and displays the hallmark phenotype of hypertrophic cardiomyopathy (PMID: 19590044). Based on the available evidence, the c.772G>A (p.Glu258Lys) variant is classified as pathogenic for hypertrophic cardiomyopathy.
Genetics and Molecular Pathology, SA Pathology RCV000205517 SCV004175449 pathogenic Hypertrophic cardiomyopathy 2023-06-14 criteria provided, single submitter clinical testing The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 of the MYBPC3 gene which is predicted to change the amino acid glutamic acid at position 258 in the protein to lysine. The variant has been reported in excess of 70 probands with a clinical presentation of hypertrophic cardiomyopathy (PS4) and is reported to segregate with disease in multiple families (PMID#9562578, 16858239). Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044) (PS3). This variant has been reported in dbSNP (rs397516074), reported as disease causing in the HGMD database (CM981322) and is reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 42792).
All of Us Research Program, National Institutes of Health RCV000205517 SCV004834726 pathogenic Hypertrophic cardiomyopathy 2023-11-20 criteria provided, single submitter clinical testing This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 14563344, 12974739, 15114369, 15563892, 16858239, 1853307, 19808356, 19574547, 22267749, 23233322, 30645170, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000161125 SCV000733061 pathogenic Hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158310 SCV000924856 pathogenic not provided 2015-10-28 no assertion criteria provided provider interpretation
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000158310 SCV001954161 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein RCV002290957 SCV002583319 pathogenic Left ventricular noncompaction 10 2021-11-02 no assertion criteria provided clinical testing

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