ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1591G>C (p.Gly531Arg)

gnomAD frequency: 0.00006  dbSNP: rs397515912
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Total submissions: 16
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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 RCV000035416 SCV000059064 likely pathogenic Hypertrophic cardiomyopathy 2023-07-19 criteria provided, single submitter clinical testing The p.Gly531Arg variant in MYBPC3 has been reported in association with two distinct nucleotide changes: c.1591G>C and c.1591G>A. Considering both nucleotide changes, this variant has been reported in 1 individual with dilated cardiomyopathy (DCM; c.1591G>A; Waldmuller 2011 PMID: 21750094) and in over 10 individuals with hypertrophic cardiomyopathy (HCM; c.1591G>A: Girolami 2006 PMID: 16858239, Olivotto 2008 PMID: 18533079, Garcia-Castro 2009 PMID: 19150014, Michels 2011, Waldmuller 2011 PMID: 21750094, Walsh 2017 PMID: 27532257, LMM data; c.1591G>C: Millat 2010 PMID: 20624503, Olivotto 2011 PMID: 21835320, Coto 2012 PMID: 22765922, Rubattu 2016 PMID: 27483260, LMM data). Of the individuals with HCM, at least 4 individuals carried a second pathogenic MYBPC3 variant and had early onset disease (LMM data, Millat 2010 PMID: 20624503, Rubattu 2016 PMID: 27483260). Furthermore, the c.1591G>C variant was found by our laboratory to segregate with disease in 2 affected relatives from 1 family. This variant has also been reported by other clinical laboratories in ClinVar (Variation IDs: 164109 (c.1591G>A) and 42550 (c.1591G>C)). Additionally, the c.1591G>A variant has been identified in 0.01% (2/15288) of Latino and in 0.002% (1/41450) of African/African American chromosomes by gnomAD, while the c.1591G>C variant has been identified in 0.004% (3/68034) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org, v.3.1.2). A functional study in which the c.1591G>C (p.Gly531Arg) variant was transfected into MYBPC3 knockout mouse cardiomyocytes alone and in combination with wild-type MYBPC3 (to represent homozygous and heterozygous disease states) revealed abnormal contractile force in both scenarios compared to wild-type (Wijnker 2016 PMID: 27108529). Computational prediction tools and conservation analysis also suggest that the variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PS3_Moderate, PP3.
GeneDx RCV000505710 SCV000208365 likely pathogenic not provided 2023-08-08 criteria provided, single submitter clinical testing Reported in several individuals with cardiomyopathy in published literature and at GeneDx (Millat et al., 2010; Olivotto et al., 2011; Lopes et al., 2015; Rubattu et al., 2016; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies examining the effect of c.1591 G>C in mouse-derived engineered heart tissue demonstrated that tissue expressing the variant is associated with a hypercontractile phenotype compared to wild type cardiac tissue (Wijnker et al., 2016); This variant is associated with the following publications: (PMID: 28241245, 25351510, 23690394, 20624503, 19150014, 27532257, 23508784, 27483260, 28193612, 16858239, 22765922, 21835320, 28798025, 34426522, 32841044, 35208637, 35753512, 35433691, 27108529, 36291626, 35130036)
CeGaT Center for Human Genetics Tuebingen RCV000505710 SCV001148277 likely pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing MYBPC3: PS1, PS3:Supporting, PS4:Supporting
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000999623 SCV001156330 likely pathogenic Wolff-Parkinson-White pattern; Hypertrophic cardiomyopathy 2018-02-09 criteria provided, single submitter research MYBPC3 Gly531Arg variant has been reported as two nucleotide changes: c.1591G>C and c.1591G>A. When considered together this variant has been identified in 1 DCM proband (Waldmuller S, et al., 2011) and more than 10 individuals with HCM and no other pathogenic variants (Girolami F, et al., 2006; Ho CY, et al., 2009; Michels M, 2011; Waldmuller S, et al., 2011; Olivotto I, et al., 2011; Coto E, et al., 2012; Bos JM, et al., 2014; Lopes LR, et al., 2015; Rubattu S, et al., 2016; Walsh R, et al., 2017; LMM, Pers. Comm.; GeneDx, Pers. Comm.) The variant has also been found to segregate with disease in at least 1 family (LMM, Pers. Comm.). We have identified the c.1591G>C in 2 HCM probands. One proband has family history of disease in their sibling, but segregation was not possible. In the other family, the proband also harbors a second likely pathogenic TNNT2 Phe110Leu. This variant is present at a low frequency in the Genome Aggregation Database (MAF= 0.000022; http://gnomad.broadinstitute.org/). In vitro functional studies show that p.Gly531Arg causes hypercontractility in engineered heart tissue (Wijnker PJ, et al., 2016). In silico tools SIFT, PolyPhen-2 and MutationTaster predict the variant to be deleterious. In summary, the variant has been reported in numerous cases, it is rare in the general population, functional studies and in silico tools predict the variant to impact protein function, therefore we classify MYBPC3 Gly531Arg as 'Likely Pathogenic'.
Color Diagnostics, LLC DBA Color Health RCV001189212 SCV001356457 likely pathogenic Cardiomyopathy 2023-08-30 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 531 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function. In heart tissue engineered from mouse cardiac cells, this variant in heterozygous state was associated with a hypercontractile phenotype (PMID: 27108529). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 20173211, 20624503, 21835320, 23508784, 23690394, 27483260, 27532257, 27600940, 28193612, 28241245, 28986452, 31941943, 32228044, 32369506, 36291626). Two of these individuals carried a second pathogenic variant either in the same gene (PMID: 20624503) or in another gene (PMID: 32228044). This variant has also been reported in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 5/278462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant causing the same amino acid change, c.1591G>A p.Gly531Arg, is also considered to be disease-causing (ClinVar variation ID: 164109). In summary, this variant has shown a relevant phenotype in an experimental study and has been observed in multiple individuals affected with hypertrophic cardiomyopathy. Based on available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV000035416 SCV001574033 likely pathogenic Hypertrophic cardiomyopathy 2023-12-19 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 531 of the MYBPC3 protein (p.Gly531Arg). This variant is present in population databases (rs397515912, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 20624503, 21750094, 23508784, 24793961, 25524337, 27483260, 27532257, 27600940, 28356264, 30297972). ClinVar contains an entry for this variant (Variation ID: 42550). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001189212 SCV002042131 pathogenic Cardiomyopathy 2022-05-31 criteria provided, single submitter clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health RCV000035416 SCV002522181 likely pathogenic Hypertrophic cardiomyopathy 2021-08-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271383 SCV002556034 likely pathogenic Primary familial hypertrophic cardiomyopathy 2022-06-02 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.1591G>C (p.Gly531Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247086 control chromosomes (gnomAD). c.1591G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Girolami_2006, Olivotto_2011, Coppini_2014, Rubattu_2016, Ho_2018). These data indicate that the variant may be associated with disease. Co-occurrences with other pathogenic variant have been reported (MYBPC3 c.2309-2A>G, Rubattu_2016), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, via measuring contraction forces in an engineered heart tissue assay from MYBPC3-knock out mice. Human wild-type and variant MYBPC3 was transduced into the engineered heart tissue and contraction was assayed at varying Ca2+ levels. The variant failed to rescue the hypercontractile phenotype seen in non-transduced (MYBPC3 null) samples, when expressed either alone or jointly with wild-type MYBPC3, demonstrating the variant may also act in a dominant-negative manner (Wijnker_2016). Seven ClinVar submitters have assessed the variant since 2014: all seven classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV002286698 SCV002577577 pathogenic Hypertrophic cardiomyopathy 4 2022-05-16 criteria provided, single submitter clinical testing PS1, PM2, PM1, PP3, PP5
Ambry Genetics RCV002399369 SCV002705733 likely pathogenic Cardiovascular phenotype 2024-01-30 criteria provided, single submitter clinical testing The p.G531R variant (also known as c.1591G>C), located in coding exon 17 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 1591. The glycine at codon 531 is replaced by arginine, an amino acid with dissimilar properties. This variant and another variant leading to the same amino acid substitution (MYBPC3 c.1591G>A) have been reported in multiple unrelated patients with hypertrophic cardiomyopathy (HCM) (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Millat G et al. Eur J Med Genet, 2010 Jul;53:261-7; Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Lopes LR et al. Heart, 2015 Feb;101:294-301; Rubattu S et al. Int J Mol Sci, 2016 Jul;17:[ePub ahead of print]; Walsh R et al. Genet Med, 2017 Feb;19:192-203; external communication; Ambry internal data). In a functional study utilizing engineered heart tissue derived from MYBPC3 knockout cardiomyocytes, c.1591G>C p.G531R was unable to completely rescue the hypercontractile phenotype of the knockout tissue; however, the physiological relevance of this result is unclear (Wijnker PJ et al. J. Mol. Cell. Cardiol. 2016;97:82-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002286698 SCV002769189 uncertain significance Hypertrophic cardiomyopathy 4 2020-06-11 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from a glycine to an arginine (exon 17). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD v2 <0.001 (5 heterozygotes, 0 homozygotes). A different nucleotide substitution resulting in the same amino acid change has also been observed in gnomAD v2 (8 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v3 (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (C3 domain; PMID: 27108529). (N) 0705 - No comparable variants have previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a tryptophan has been reported as a VUS by a research laboratory in an individual with mild concentric hypertrophy but not diagnostic of hypertrophic cardiomyopathy (HCM) (ClinVar). (N) 0808 - Previous reports of pathogenicity are conflicting (ClinVar, PMID: 28986452). Both G>C and G>A nucleotide changes have been reported as likely pathogenic and as VUS variants, in individuals with HCM (PMID: 27483260; 27108529) and dilated cardiomyopathy (DCM) (ClinVar). Some individuals were also reported to have a second pathogenic variant in a sarcomere gene (PMID: 31941943). (N) 1002 - Moderate functional evidence supporting abnormal protein function (PMID: 27108529). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics RCV002496528 SCV002810881 likely pathogenic Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2021-10-10 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV002286698 SCV003842222 likely pathogenic Hypertrophic cardiomyopathy 4 2023-03-20 criteria provided, single submitter clinical testing homozygous case; clinical and carrier status of parents are unkown
Institute of Human Genetics, University of Leipzig Medical Center RCV002286698 SCV003925621 pathogenic Hypertrophic cardiomyopathy 4 2023-03-31 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous with NM_000256.3:c.1591G>C._x000D_ Criteria applied: PS1, PS4, PM2_SUP, PP3
All of Us Research Program, National Institutes of Health RCV000035416 SCV004842467 likely pathogenic Hypertrophic cardiomyopathy 2024-01-08 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 531 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function. In heart tissue engineered from mouse cardiac cells, this variant in heterozygous state was associated with a hypercontractile phenotype (PMID: 27108529). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 20173211, 20624503, 21835320, 23508784, 23690394, 27483260, 27532257, 27600940, 28193612, 28241245, 28986452, 31941943, 32228044, 32369506, 36291626). Two of these individuals carried a second pathogenic variant either in the same gene (PMID: 20624503) or in another gene (PMID: 32228044). This variant has also been reported in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 5/278462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant causing the same amino acid change, c.1591G>A p.Gly531Arg, is also considered to be disease-causing (ClinVar variation ID: 164109). In summary, this variant has shown a relevant phenotype in an experimental study and has been observed in multiple individuals affected with hypertrophic cardiomyopathy. Based on available evidence, this variant is classified as Likely Pathogenic.

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