Submissions for variant NM_000256.3(MYBPC3):c.3742G>A (p.Gly1248Arg)

gnomAD frequency: 0.00007  dbSNP: rs202147520

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035614	SCV000059265	uncertain significance	not specified	2018-03-06	criteria provided, single submitter	clinical testing	The p.Gly1248Arg variant in MYBPC3 has been reported in at least 2 individuals w ith DCM (Cuenca 2016, Forleo 2017), 2 individuals with unexplained sudden death (Christiansen 2016, Neubauer 2017), and 2 individuals with HCM, including 1 chil d who carried a splice variant in MYBPC3 (Hofman 2007, Morita 2008, Coto 2012, G omez 2017). However, the variant failed to segregate with DCM in 2 affected memb ers of 1 family (Cuenca 2016). This variant has also been identified in 0.005% (6/111626) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs202147520). Computational prediction to ols suggest that the p.Gly1248Arg variant may impact the protein, though conserv ation analysis show 2 mammals (orangutan and elephant) carry an arginine (Arg) a t position 1248, suggesting that this change may be tolerated. Splice prediction tools predict that this variant may create a novel 3' splice site, though in vi tro functional studies do not support a splicing impact (Ito 2017). In summary, the clinical significance of the p.Gly1248Arg variant is uncertain. ACMG/AMP Cri teria applied: BS4.
GeneDx	RCV000766378	SCV000208191	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Reported in association with DCM, including one family where the variant did not segregate with disease in two affected family members (Cuenca et al., 2016; Forleo et al., 2017; van Lint et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance by several other clinical laboratories (ClinVar Variant ID#42739; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21415409, 27532257, 23299917, 18403758, 25637381, 17908752, 22765922, 27650965, 26899768, 28356264, 28750076, 28074886, 28679633, 30847666, 32841044, 33190526, 29773157, 32009526, 33782553, 30696458)
Invitae	RCV000529357	SCV000623607	uncertain significance	Hypertrophic cardiomyopathy	2023-12-06	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 1248 of the MYBPC3 protein (p.Gly1248Arg). This variant is present in population databases (rs202147520, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 22765922). ClinVar contains an entry for this variant (Variation ID: 42739). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change does not affect mRNA splicing (PMID: 28679633). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000148669	SCV000747929	uncertain significance	Primary familial hypertrophic cardiomyopathy	2016-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183748	SCV001349564	uncertain significance	Cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1248 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional mini-gene assay has shown that this variant may not cause aberrant splicing (PMID: 28679633). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 22765922, 27532257, 28356264, 30696458, 32841044, 33190526, 33495596, 33495597, ClinVar SCV000747929.1) including one individual who also carried a pathogenic variant in the MYBPC3 gene (PMID: 33190526). This variant has also been reported in three individuals affected with dilated cardiomyopathy (PMID: 26899768, 28750076, 30847666), in one individual affected with cardiomyopathy (PMID: 32009526), and in four young individuals affected with sudden cardiac death (PMID: 17908752, 27650965, 28074886, 37589201) including one carrying a pathogenic MYBPC3 splice variant (PMID: 17908752). This variant has been identified in 8/249120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035614	SCV001623259	uncertain significance	not specified	2021-05-03	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3742G>A (p.Gly1248Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249620 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3742G>A has been reported in the literature in individuals affected with hypertrophic cardiomyopathy or dilated cardiomyopathy (Hofman_2007, Morita_2008, Coto_2012, Cuenca_2016, Walsh_2017, Gomez_2017, Forleo_2017, Ware_2018, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, one co-occurrence with another pathogenic variant has been reported (MYBPC3 c.2149-2delA; Hofman_2007), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002490483	SCV002784196	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-16	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148669	SCV000190393	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766378	SCV001978677	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766378	SCV001978755	uncertain significance	not provided		no assertion criteria provided	clinical testing