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

gnomAD frequency: 0.00006  dbSNP: rs121909374

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000199033	SCV000059072	pathogenic	Hypertrophic cardiomyopathy	2020-04-14	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158104	SCV000208039	pathogenic	not provided	2022-11-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); A study of fetal rat cardiomyocytes suggests that p.(E542Q) may have a dominant negative effect on sarcomere function (Flavigny et al., 1999); This variant is associated with the following publications: (PMID: 18533079, 30645170, 31198128, 23299917, 22057632, 15519027, 20378854, 19150014, 12707239, 18761664, 16199542, 21839045, 24793961, 20433692, 24093860, 25637381, 25031304, 27483260, 9048664, 26441228, 26936621, 28658286, 28538763, 28611029, 28193612, 28408708, 28790153, 28615295, 27532257, 28679633, 29511324, 29121657, 30609409, 29790872, 31006259, 31514951, 31996869, 31447099, 26822237, 24704860, 33500567, 31589614, 32731933, 32686758, 33673806, 34135346, 34495297, 34097875, 10610770)
Invitae	RCV000199033	SCV000253809	pathogenic	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 542 of the MYBPC3 protein (p.Glu542Gln). This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121909374, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9048664, 9631872, 15519027, 16199542, 18533079, 20433692, 25031304, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1679G>C. ClinVar contains an entry for this variant (Variation ID: 8608). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 9048664, 22057632, 25031304). For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000201915	SCV000256661	pathogenic	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	2021-10-22	criteria provided, single submitter	clinical testing	The c.1624G>C pathogenic mutation (also known as p.E542Q), located in coding exon 17 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 1624. This change occurs in the last base pair of coding exon 17, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glutamic acid at codon 542 to glutamine, an amino acid with highly similar properties. Studies using cDNA from patient lymphocytes have reported the mutation resulted in skipping of exon 17, leading to a premature stop codon (Carrier L et al. Circ Res. 1997;80(3):427-34; Singer ES et al. Circ Genom Precis Med. 2019 01;12(1):e002368). Another in vitro study evaluated mRNA from human cardiac muscle in patients with this mutation and showed one full-length missense mutant mRNA product and one nonsense mRNA product resulting from skipping of exon 17 (alteration reported as c.1679G>C) (Marston S et al. J Muscle Res Cell Motil. 2012;33(1): 75-80). This mutation has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and shown to segregate with disease in at least three families (Carrier L et al. Circ Res. 1997;80(3):427-34; García-Castro M et al. Rev Esp Cardiol. 2009;62(1):48-56; Rodríguez-García MI et al. BMC Med Genet. 2010;11:67; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]). This alteration was reported in families who also had a second mutation in MYBPC3 and presented with severe HCM or sudden death (Saltzman AJ et al. Circ Res. 2010;106(9):1549-52; Rafael JF et al. Arq. Bras. Cardiol. 2017 Apr;108(4):354-360). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000009139	SCV000494449	pathogenic	Hypertrophic cardiomyopathy 4	2016-03-30	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000009139	SCV000584103	pathogenic	Hypertrophic cardiomyopathy 4	2015-12-10	criteria provided, single submitter	research
Phosphorus, Inc.	RCV000009139	SCV000679775	pathogenic	Hypertrophic cardiomyopathy 4	2017-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000627130	SCV000747943	pathogenic	Primary familial dilated cardiomyopathy	2017-04-24	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000009139	SCV000993585	pathogenic	Hypertrophic cardiomyopathy 4	2019-10-10	criteria provided, single submitter	research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000009139	SCV001132521	pathogenic	Hypertrophic cardiomyopathy 4	2019-03-28	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170957	SCV001333612	pathogenic	Cardiomyopathy	2023-03-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170957	SCV001343368	pathogenic	Cardiomyopathy	2023-02-23	criteria provided, single submitter	clinical testing	This variant changes the last nucleotide c.G of the Ig-like domain C3 of exon 17 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 17 splice donor site. RNA studies have shown that this variant causes skipping of exon 17 and introduces a premature translation stop codon (PMID: 9048664, 22057632, 25031304, 34097875). An experimental functional study has shown that the truncated protein causes decreased protein incorporation into the sarcomere (PMID: 10610770). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy (PMID: 9048664, 9631872, 12707239, 15519027, 16199542, 18533079, 19150014, 20433692, 25031304, 27483260, 27532257) and segregated with disease in 6 affected relatives across 2 families (PMID: 9048664). This variant has been identified in 5/262678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000009139	SCV001434956	pathogenic	Hypertrophic cardiomyopathy 4	2019-10-30	criteria provided, single submitter	clinical testing	The c.1624G>C (p.Glu542Gln) variant in exon 17 of the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (HCM) (PMID: 9631872, 12707239, 15519027, 16199542, 16858239, 19150014, 20738943, 21239446, 18533079, 24093860, 27483260, 27532257). It has also been reported to segregate with disease in multiple affected individuals from unrelated families (PMID: 9048664, 20433692). This variant has an extremely low frequency in general population databases. The c.1624G>C sequence change is located at the last base of the exon and predicted to alter gene splicing. mRNA studies using patient lymphocytes and cardiac tissues have confirmed that this variant causes skipping of exon 17, introducing a premature translational termination codon, while normally spliced missense transcript for c.1624G>C (p.Glu542Gln) is also expressed (PMID: 9048664, 22057632, 25031304, 28679633). Functional studies in fetal rat cardiomyocytes showed that incorporation of truncating variants of MYBPC3 into sarcomere is reduced compared to wild-type and suggested that truncating variants and the c.1624G>C (p.Glu542Gln) missense variant have a dominant negative effect on the myobrillar architecture (PMID: 10610770). In summary, this c.1624G>C (p.Glu542Gln) variant in the MYBPC3 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000158104	SCV001447952	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000009139	SCV001984871	pathogenic	Hypertrophic cardiomyopathy 4	2020-07-07	criteria provided, single submitter	clinical testing	This variant affects the last nucleotide of exon 17 of MYBPC3 and is likely to interfere with native splicing. This variant has been previously reported mainly as a heterozygous variant in unrelated families with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and also as a compound heterozygous change in patients with HCM (PMID: 29121657, 27532257, 31514951, 16199542, 20378854). Expression studies using mRNA from patient myocardial tissue demonstrate that this variant leads to exon skipping (PMID: 25031304) and decreased protein incorporation into the A-band of the sarcomere (PMID: 10610770). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/262678) and thus is presumed to be rare. The c.1624G>C (p.Glu542Gln) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1624G>C (p.Glu542Gln) variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000158104	SCV002017652	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000158104	SCV002503365	pathogenic	not provided	2022-02-08	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000009139	SCV002762765	pathogenic	Hypertrophic cardiomyopathy 4	2022-11-09	criteria provided, single submitter	research	ACMG codes:PVS1_VeryStrong, PS3_Supporting, PS4_Moderate, PM2_Moderate, PP1_Strong
Fulgent Genetics, Fulgent Genetics	RCV000505586	SCV002814679	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-03-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003332998	SCV004040644	pathogenic	Left ventricular noncompaction 10	2023-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000009139	SCV004040787	pathogenic	Hypertrophic cardiomyopathy 4	2023-03-29	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387501	SCV004099224	pathogenic	MYBPC3-related disorder	2023-07-19	criteria provided, single submitter	clinical testing	PM2, PP1, PS3_VeryStrong
Illumina Laboratory Services, Illumina	RCV000009139	SCV004101361	pathogenic	Hypertrophic cardiomyopathy 4	2023-08-24	criteria provided, single submitter	clinical testing	The MYBPC3 c.1624G>C (p.Glu542Gln) missense variant has been identified in individuals with hypertrophic cardiomyopathy (PMID: 9048664; 9631872; 27532257; 30645170; 36264615). This variant has been shown to segregate with disease in at least two families (PMID: 9048664). The p.Glu542Gln variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies conducted in patient cells and non-human cells demonstrate that this variant results in abnormal splicing of exon 17 leading to a truncated protein that lacks the titin and myosin binding sites (PMID: 9048664; 25031304; 30645170; 34097875). Based on the available evidence, the c.1624G>C (p.Glu542Gln) variant is classified as pathogenic for hypertrophic cardiomyopathy.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000009139	SCV004177148	pathogenic	Hypertrophic cardiomyopathy 4	2023-08-02	criteria provided, single submitter	clinical testing	The MYBPC3 c.1624G>C (p.Glu542Gln) variant has been observed in individuals with hypertrophic cardiomyopathy and has been shown to segregate with disease in affected families (Carrier L et al., PMID: 9048664; Charron P et al., PMID: 9631872; Van Driest L et al., PMID: 15519027; Ingles J et al., PMID: 16199542; Olivetto I et al., PMID: 18533079; Rodríguez-García M et al., PMID: 20433692; Helms A et al., PMID: 25031304; Walsh R et al., PMID: 27532257). Functional studies show that this misssense variant, which sits next to a consensus splice site, alters splicing and results in nonsense mediated decay (Carrier L et al., PMID: 9048664; Martson S et al., PMID: 22057632; Helms A et al., PMID: 25031304). This variant is only observed on 5/262,678 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MYBPC3 function. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000158104	SCV004226848	pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing	PP1, PS3, PS4
OMIM	RCV000009139	SCV000029356	pathogenic	Hypertrophic cardiomyopathy 4	1997-03-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000035424	SCV000190378	pathogenic	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Blueprint Genetics	RCV000035424	SCV000207041	pathogenic	Primary familial hypertrophic cardiomyopathy	2014-10-27	no assertion criteria provided	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.
Donald Williams Parsons Laboratory, Baylor College of Medicine	RCV000505586	SCV000599924	pathogenic	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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000009139	SCV001468139	pathogenic	Hypertrophic cardiomyopathy 4	2020-06-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158104	SCV001954605	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158104	SCV001970359	pathogenic	not provided		no assertion criteria provided	clinical testing