11-47332204-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6
The NM_000256.3(MYBPC3):c.3682C>T(p.Arg1228Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1228H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3682C>T | p.Arg1228Cys | missense_variant | 33/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3682C>T | p.Arg1228Cys | missense_variant | 33/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.3682C>T | p.Arg1228Cys | missense_variant | 32/34 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000591 AC: 90AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000177 AC: 44AN: 249234Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 135220
GnomAD4 exome AF: 0.000262 AC: 383AN: 1461522Hom.: 0 Cov.: 33 AF XY: 0.000254 AC XY: 185AN XY: 727048
GnomAD4 genome AF: 0.000591 AC: 90AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2020 | This variant is associated with the following publications: (PMID: 31006259, 29121657, 24503780, 28679633, 27896284, 25351510, 23861362, 22958901, 24447051, 22464770, 25637381, 20474083) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 23, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 18, 2016 | The p.Arg1228Cys variant in MYBPC3 has been identified in 8/3600 individuals of unspecified clinical phenotype from the Framingham and Jackson Heart Studies (Bi ck 2012). It has also been identified in 0.1% (13/9766) of African chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201312636). Additionally, this variant has been identified by our laboratory i n 7 individuals (4 with DCM; 1 with HCM; 1 with early onset severe left ventricu lar dysfunction/ biventricular dilation and 1 with an unspecified complex cardia c phenotype), though it did not segregate with disease in 1 of 3 affected indivi duals from 1 family. This amino acid is not well conserved in evolution which su ggests a change at this amino acid may be tolerated. Collectively, these data su pport that the p.Arg1228Cys variant is less likely disease-causing, though addit ional studies are needed to fully assess its clinical significance. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2022 | Variant summary: MYBPC3 c.3682C>T (p.Arg1228Cys) results in a non-conservative amino acid change in 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 0.0006 in 150976 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. The variant, c.3682C>T, has been reported in the literature in individuals affected with cardiomyopathy, including both dilated- and hypertrophic cardiomyopathy (see e.g. in HGMD), however, in at least one family, lack of co-segregation with the disease phenotype (DCM) was noted (Lakdawala_2012). At least one publication reported experimental evidence evaluating an impact on protein structure, and demonstrated that the variant didn't impact domain stability (Suay-Corredara_2021). Ten submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as VUS (n=5), likely benign (n=4) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign. - |
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 08, 2015 | 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.Arg1228Cys Given the weak case data, failure to segregate, and presence in general population samples, we consider this a variant of uncertain significance. This variant has not been reported in published literature. In a publication on the Laboratory for Molecular Medicine’s (LMM) experience with sequencing for DCM, this variant is noted in a table of variants for which genotyping probes were added to the chip (Zimmerman et al 2010). The Seidmans reported on the occurrence of this variant in the Jackson Heart Study (Bick et al 2012). They found that individuals with multiple rare MYBPC3 variants (including this variant) had a 14-15% lower left ventricular wall thickness. This is a semi-conservative amino acid change with a positively charged Arginine replaced with a neutral Cysteine. This replacement could affect disulfide bonding in the resulting protein. In silico analysis (PolyPhen2) predicts this amino acid change to be probably damaging to the structure/function of the protein. Arginine is highly conserved at this position across species. In total the variant has been seen in ~7 of 6664 laboratory controls and individuals from publicly available population datasets. It is most frequent in African American samples with 0.25% of such individuals carrying the variant. The variant was reported online in 2 of 4137 Caucasian individuals and 5 of 1933 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 7th, 2014). 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. It is listed in dbSNP (rs201312636) with entries for the ESP data and the exome chip designed from the ESP data. - |
Hypertrophic cardiomyopathy 4 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | MYBPC3 NM_000256.3 exon 33 p.Arg1228Cys (c.3682C>T): This variant has been reported in the literature in several individuals with cardiomyopathy (HCM, DCM, LVNC) (Zimmerman 2010 PMID:20474083, Lakdawala 2012 PMID:22464770, Pugh 2014 PMID:24503780, Paterick 2014 PMID:24447051, Lopes 2015 PMID:25351510). However, this variant failed to segregate with disease in at least one family (Lakdawala 2012 PMID:22464770). This variant is also present in 0.1% (33/24194) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/11-47353755-G-A) and is present in ClinVar (Variation ID:161306). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
MYBPC3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 21, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 31, 2019 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at