Submissions for variant NM_000256.3(MYBPC3):c.13G>C (p.Gly5Arg)

gnomAD frequency: 0.00055  dbSNP: rs201278114

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000474218	SCV000054780	uncertain significance	Hypertrophic cardiomyopathy	2018-04-05	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151176	SCV000198995	likely benign	not specified	2018-05-18	criteria provided, single submitter	clinical testing	The p.Gly5Arg variant in MYBPC3 is classified as likely benign because it has be en identified in 0.06% (75/120166) of European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201278114). Pl ease note: this variant has been reported in individuals with various cardiomyop athies (8 HCM/LVH, 2 DCM, 1 LVNC; Berge 2014, Hershberger 2010, Keeling 2010, M orita 2006, Probst 2011, Van Driest 2004, Villacorta 2014, LMM data). Due to the frequency of this variant, it would be expected, by chance, that some individua ls with cardiomyopathy may carry this variant. Furthermore, four of the individu als with HCM described above also carried pathogenic loss-of-function variants i n the MYBPC3 gene, sufficient to explain their cardiomyopathy (Berge 2014, Van D riest 2004, Villacorta 2014, LMM data). ACMG/AMP Criteria applied: BS1; BP5.
GeneDx	RCV000727089	SCV000208251	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Invitae	RCV000474218	SCV000546449	uncertain significance	Hypertrophic cardiomyopathy	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the MYBPC3 protein (p.Gly5Arg). This variant is present in population databases (rs201278114, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC) (PMID: 15519027, 21551322, 24111713, 24795128). ClinVar contains an entry for this variant (Variation ID: 161305). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect MYBPC3 function (PMID: 21297165). 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.
Eurofins Ntd Llc (ga)	RCV000727089	SCV000705558	uncertain significance	not provided	2017-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621024	SCV000736501	likely benign	Cardiovascular phenotype	2021-10-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000771804	SCV000904503	likely benign	Cardiomyopathy	2019-10-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000988560	SCV001138326	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151176	SCV001448496	uncertain significance	not specified	2020-11-24	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.13G>C (p.Gly5Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 232870 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (0.0003 vs 0.001), allowing no conclusion about variant significance. c.13G>C has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, as well as in unaffected individuals (Van Driest_2004, Morita_2006, Keeling_2010, Probst_2011, Berge_2013, Villacorta_2013, Pugh_2014, Methner_2016, Gomez_2017, Ko_2017, Norrish_2019). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic MYBPC3 variants have been reported (MYBPC3 c.1504C>T, p.Arg502Trp; MYBPC3 c.3066dupC, p.N1023fs*28) (Van Driest_2004, Villacorta_2013), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Matsuyama_2018). Ten ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x), uncertain significance (7x) and pathogenic (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771804	SCV002042126	uncertain significance	Cardiomyopathy	2022-07-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727089	SCV002050270	uncertain significance	not provided	2021-10-23	criteria provided, single submitter	clinical testing	The MYBPC3 c.13G>C, p.Gly5Arg variant (rs201278114) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (Berge 2014, Van Driest 2004, Villacorta 2014), dilated cardiomyopathy (Hershberger 2010), and LVNC (Probst 2011). However, this variant was found to co-occur with an additional pathogenic MYBPC3 variant in two cases (Van Driest 2004, Villacorta 2014). One functional study demonstrated the variant protein maintains wild type binding to Fhod3 (Matsuyama 2018). This variant is also reported in ClinVar (Variation ID: 161305) and is found in the non-Finnish European population with an allele frequency of 0.06% (73/121166 alleles) in the Genome Aggregation Database. The glycine at codon 5 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.186). Due to limited information, the clinical significance of the p.Gly5Arg variant is uncertain at this time. References: Berge KE, Leren TP. Genetics of hypertrophic cardiomyopathy in Norway. Clin Genet. 2014 Oct;86(4):355-60. PMID: 24111713. Hershberger RE et al. Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ Cardiovasc Genet. 2010 Apr;3(2):155-61. PMID: 20215591. Matsuyama S et al. Interaction between cardiac myosin-binding protein C and formin Fhod3. Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4386-E4395. PMID: 29686099. Probst S et al. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ Cardiovasc Genet. 2011 Aug 1;4(4):367-74. PMID: 21551322. Van Driest SL et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Nov 2;44(9):1903-10. PMID: 15519027. Villacorta E et al. Usefulness of genetic diagnosis in a woman with hypertrophic cardiomyopathy and the desire for motherhood. Rev Esp Cardiol (Engl Ed). 2014 Feb;67(2):148-50. PMID: 24795128.
CeGaT Center for Human Genetics Tuebingen	RCV000727089	SCV004698913	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MYBPC3: BP4, BP5
CSER _CC_NCGL, University of Washington	RCV000148668	SCV000190392	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	RCV000234987	SCV000263122	pathogenic	Left ventricular hypertrophy	2015-03-28	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000727089	SCV000925169	uncertain significance	not provided	2017-04-12	no assertion criteria provided	provider interpretation	Patient is a teenage Caucasian male with a recent history of palpitations and a diagnosis of LVNC on cardiac MRI, but with normal biventricular size and function. Genetic testing was done at Invitae laboratory. p.Gly5Arg (G5R; c.13G>C) in exon 1 of the MYBPC3 gene (NM_000256.3) Chromosome location 11:47374186 C / G Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk family members. In summary, this variant has been reported in several individuals with various cardiomyopathies, yet a fair number of those individuals also carry a second pathogenic variant sufficient to explain their disease. There is only very weak published segregation data: specifically, segregating in one family member with a borderline phenotype in just one family (Villacorta et al. 2014). Furthermore, Gly5Arg is found in the population at an appreciable frequency, and changes a residue that is not well conserved across species. For those reasons, we think it is unlikely to cause disease. The Gly5Arg variant has been reported in at least 7 individuals with various forms of cardiomyopathy (5 HCM, 1 DCM, 1 LVNC). Of note: Three of the individuals with HCM also had a separate, convincingly pathogenic variant in MYBPC3. Van Driest et al. (2004) reported the variant in a proband with HCM who also had a pathogenic Arg502Trp variant in the MYBPC3 gene. Keeling et al. (2010) reported it in one individual with HCM (septal thickness 2.2 cm). Berge & Loren (2014) reported it in two Norwegian probands with HCM, one of whom also had a pathogenic truncating variant in MYBPC3 (Ser311*). Villacorta et al. from Spain reported it in a woman with HCM who also had a truncating variant in MYBPC3 in trans: Asn1023fs+28*. The truncating variant segregated with disease in the patient’s 37-year-old affected brother (septal thickness 1.9 cm, cardiac fibrosis on MRI) while Gly5Arg was not present in him. Their father, who at age 63 had borderline septal hypertrophy of 1.6 cm, a PW thickness of 1.0 cm, and a history of hypertension, had the Gly5Arg variant (which the authors interpreted as disease-causing). Their mother had the truncating variant and a normal echocardiogram. Hershberger et al. reported it in a patient with familial DCM, however no family members were available for segregation analysis. Probst et al. (2011) reported it in a proband with chest pain and left ventricular non-compaction (LVNC) as well as the patient’s 47-year-old unaffected mother. In addition, Morita et al. (2006) reported the variant in a participant in the Framingham Heart Study who had somewhat increased left ventricular wall thickness of >1.3 cm but no known diagnosis of HCM; it was also present in an elderly sibling with normal LV wall thickness. This is a non-conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a positively-charged Arginine. Glycine at this location is not well conserved across vertebrate species. It is frequently an Alanine, Valine, or Threonine instead. Arginine is, in fact, the default amino acid in at least one mammalian species. LMM reports that the change to Arginine was predicted to be benign using their computational tool clinically validated for HCM variants. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). Loss of function variants, such as protein-truncating variants, in the MYBPC3 gene are a well-known cause of cardiomyopathy, while certain missense variants may be tolerated. One experimental study suggests that the Gly5Arg missense change does not have an effect on MYBPC3 protein binding to myosin (Ratti et al. 2011). In total the variant has been seen in at least 85 of 131,396 published controls and individuals from publicly available population datasets. The variant was not observed in 926 published controls: 200 (100 Caucasian, 100 African American) in Van Driest et al 2004; 300 in Morita et al 2006; 246 (186 white, 23 Yoruban, 19 Asian, 18 Hispanic) in Hershberger et al 2010; 180 in Probst et al 2011. This variant was reported online in 85 individuals in the gnomAD database, which includes variant calls on 130,470 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, it was in in 75/60,083 individuals with non-Finnish European ancestry. It was also observed in 8/11,395 African and 2/15,617 Latino ancestry individuals. The overall allele frequency in gnomAD was 0.033% and the highest allele frequency was 0.062% in Europeans. For context: Whiffin et al (2016 pre-print) proposed that MYBPC3 variants with frequency greater than 0.004% are unlikely to be pathogenic for hypertrophic cardiomyopathy (HCM). The phenotype of those participants is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.