Submissions for variant NM_000256.3(MYBPC3):c.442G>A (p.Gly148Arg)

gnomAD frequency: 0.00011  dbSNP: rs397516050

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172015	SCV000054778	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000172015	SCV000059278	uncertain significance	not provided	2022-04-18	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000172015	SCV000208215	likely pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	In silico analyses support that this missense variant does not alter protein structure/function but has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25210889, 22267749, 18409188, 20474083, 20530761, 30291343, 25335496, 27650965, 20378854, 23861362, 27532257, 28794111, 28679633, 28790153, 29988065, 29447731, 29121657, 29709087, 31293105, 30847666, 32480058, 36243179, 33662488, 35288587, 33782553, 36264615, 37652022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206268	SCV000259913	uncertain significance	Hypertrophic cardiomyopathy	2024-01-31	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 148 of the MYBPC3 protein (p.Gly148Arg). This variant is present in population databases (rs397516050, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM), left ventricular noncompaction cardiomyopathy (LVNC) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20378854, 20530761, 22267749, 25210889, 27532257, 29709087, 30847666, 32480058, 32588587). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42752). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Phosphorus, Inc.	RCV000578062	SCV000679776	likely pathogenic	Hypertrophic cardiomyopathy 4	2017-08-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000578062	SCV000743584	pathogenic	Hypertrophic cardiomyopathy 4	2016-04-04	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000578062	SCV000744881	pathogenic	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000172015	SCV000927487	uncertain significance	not provided	2017-12-02	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845519	SCV000987622	likely pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172015	SCV001148286	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing	MYBPC3: PP3, PP4, PS3:Supporting, PS4:Supporting
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000206268	SCV001156274	uncertain significance	Hypertrophic cardiomyopathy	2018-06-05	criteria provided, single submitter	research	This MYBPC3 Gly148Arg variant has previously been identified in association with HCM (Genedx, pers. comm., May 2017; LMM, pers. comm.; Meinke P, et al., 2014; Page SP, et al., 2012; Saltzman AJ, et al., 2010), Anderson Fabry disease (Page SP, et al., 2012) and LVNC (Hoedemaekers YM, et al., 2010). Two studies identified an additional variant known to be pathogenic in the families, although both families demonstrate that Gly148Arg alone may cause HCM (Saltzman AJ, et al., 2010; Hoedemaekers YM, et al., 2010). We have identified the variant in 2 HCM probands. MYBPC3 Gly148Arg has been observed resent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0000665, which is higher than expected for disease-causing HCM variants. The variant is also present in 2 of 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts (Bick AG, et al., 2012). This missense variant is predicted to be benign by in silico tools (SIFT, PolyPhen-HCM, MutationTaster, CADD). In summary the variant has been identified in numerous HCM probands, however due to the relatively high frequency in the general population these finding may be coincidental, furthermore in silico tools predict this variant to be benign, therefore due to the conflicting evidence we classify MYBPC3 Gly148Arg as a variant of "uncertain significance".
Color Diagnostics, LLC DBA Color Health	RCV001180295	SCV001345189	uncertain significance	Cardiomyopathy	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 148 in the proline-rich domain of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). This variant has been reported in at least 19 unrelated individuals affected with hypertrophic cardiomyopathy from at least ten different families (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587). At least 4 of these affected individuals carried another pathogenic variant in the same gene or a different gene (PMID: 20378854, 20530761, 22267749, 30763825, 35288587; ClinVar SCV000059278.6); in some of these individuals, phenotype was severe or early-onset (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with hypertrophic cardiomyopathy in six heterozygous individuals from three families (PMID: 20378854, 20530761, 35288587). This variant has been observed in individuals lacking a hypertrophic cardiomyopathy phenotype (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European; 0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on the MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals in the literature. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172015	SCV001473819	likely pathogenic	not provided	2019-09-15	criteria provided, single submitter	clinical testing	The MYBPC3 c.442G>A; p.Gly148Arg variant (rs397516050) is reported in the literature in at least 19 unrelated individuals with cardiomyopathy, some of whom harbored additional uncertain or pathogenic variants in MYBPC3 or other genes associated with cardiomyopathy (Alfares 2010, Burns 2017, Page 2012, van Velzen 2017, van Waning 2018, Viswanathan 2017, Walsh 2017, Zimmerman 2010). This variant also segregated with disease in seven individuals from two families, including four individuals with childhood onset of cardiomyopathy who were also compound heterozygous for a second pathogenic variant in MYBPC3 (Hoedemaekers 2010, Saltzman 2010). This variant is predicted to create a cryptic splice acceptor site (Alamut v.2.11), which is supported by a functional mini-gene assay (Ito 2017); however, the physiological relevance of these observation is unknown. This variant is reported in ClinVar (Variation ID: 42752) and is found in the non-Finnish European population with an allele frequency of 0.015% (13/83,936 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001180295	SCV002042216	likely pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000172015	SCV002501906	uncertain significance	not provided	2021-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000845519	SCV004803348	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.442G>A (p.Gly148Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 169270 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (6.5e-05 vs 0.001), allowing no conclusion about variant significance. c.442G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Left Ventricular Noncompaction Cardiomyopathy (Fokstuen_ 2008, Hoedemaekers_2010, Saltzman_2010, Page_2012, Sabater-Molina_2013, Christiansen_2016, Burns_2017, van Velzen_2017, Walsh_ 2017, Viswanathan_2018, Alimohamed_2021, Lesurf_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33662488, 28790153, 27650965, 18409188, 20530761, 28679633, 35288587, 22267749, 20378854, 29121657, 27532257, 29661763). ClinVar contains an entry for this variant (Variation ID: 42752). Based on the evidence outlined above, the variant was classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000206268	SCV004834787	uncertain significance	Hypertrophic cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 148 in the proline-rich domain of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). This variant has been reported in at least 19 unrelated individuals affected with hypertrophic cardiomyopathy from at least ten different families (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587). At least 4 of these affected individuals carried another pathogenic variant in the same gene or a different gene (PMID: 20378854, 20530761, 22267749, 30763825, 35288587; ClinVar SCV000059278.6); in some of these individuals, phenotype was severe or early-onset (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with hypertrophic cardiomyopathy in six heterozygous individuals from three families (PMID: 20378854, 20530761, 35288587). This variant has been observed in individuals lacking a hypertrophic cardiomyopathy phenotype (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European; 0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on the MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals in the literature. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004018763	SCV004938689	uncertain significance	Cardiovascular phenotype	2022-06-03	criteria provided, single submitter	clinical testing	The c.442G>A (p.G148R) alteration is located in exon 4 (coding exon 4) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 442, causing the glycine (G) at amino acid position 148 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000578062	SCV005047007	uncertain significance	Hypertrophic cardiomyopathy 4	2024-01-05	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000578062	SCV000733076	pathogenic	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172015	SCV001923468	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172015	SCV001954861	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739324	SCV005360314	likely pathogenic	MYBPC3-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The MYBPC3 c.442G>A variant is predicted to result in the amino acid substitution p.Gly148Arg. This patient is heterozygous in the MYBPC3 gene for a sequence variant designated c.442G>A, which is predicted to result in the amino acid substitution p.Gly148Arg. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy or sudden unexplained death (Page et al. 2012. PubMed ID: 22267749; Meinke et al. 2014. PubMed ID: 25210889; Christiansen. 2016. PubMed ID: 27650965; Burns. 2017. PubMed ID: 28790153; Walsh. 2017. PubMed ID: 27532257). Additionally, this variant has been found to be in trans with a second MYBPC3 variant and segregated with hypertrophic cardiomyopathy in several family members who were heterozygous for only the c.442G>A variant (Hoedemaekers et al. 2010. PubMed ID: 20530761; Saltzman et al. 2010. PubMed ID: 20378854; van Velzen. 2017. PubMed ID: 28794111; van Waning. 2018. PubMed ID: 29447731). In silico tools and RNA sequencing data indicate this variant may impact splicing (Supplemental dataset 6 - Ito. 2017. PubMed ID: 28679633). This variant has conflicting interpretations of pathogenicity of uncertain and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42752/). Based on the available evidence, we consider the MYBPC3 c.442G>A variant to be likely pathogenic.