rs121909377
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3286G>T(p.Glu1096*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000126 in 1,588,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1096E) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 stop_gained
NM_000256.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 3.98
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-47333238-C-A is Pathogenic according to our data. Variant chr11-47333238-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333238-C-A is described in Lovd as [Pathogenic]. Variant chr11-47333238-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000484 AC: 1AN: 206580Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 111346
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GnomAD4 exome AF: 6.96e-7 AC: 1AN: 1436482Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 712138
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GnomAD4 genome 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74334
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 03, 2018 | The p.Glu1096X variant in MYBPC3 has been reported in 7 individuals with HCM, in cluding 1 individual with HCM who also carries a variant in MYH7 (Richard 1999, Richard 2003, Marsiglia 2013, Walsh 2016, LMM data). The p.Glu1096X variant was observed in isolation in 3 affected relatives (including an obligate carrier) an d in combination with the MYH7 variant in 1 affected relative. The proband and t he relative, who both carry the MYH7 and this variant, exhibited more severe dis ease compared with the other affected relatives. This variant has been identifie d in 1/11,964 African chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/; dbSNP rs121909377). This nonsense variant leads to a premature termination codon at position 1096, which is predicted to lead t o a truncated or absent protein. In summary, this variant meets criteria to be c lassified as pathogenic for HCM in an autosomal dominant manner based upon the p redicted impact of the variant, segregation studies, and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Glu1096*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10424815, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8616). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 14, 2024 | This variant changes 1 nucleotide in exon 30 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least six individuals affected with hypertrophic cardiomyopathy (PMID: 10424815, 27532257, 24093860). In one family, this variant has been detected in two individuals who also carried another pathogenic variant in the MYH7 gene and were severely affected (PMID: 10424815). This variant has been identified in 1/206580 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 16, 2024 | PP1, PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Found independently in three affected individuals from a French Caribbean family with HCM, including an obligate carrier, and co-occurred with a missense variant in the MYH7 gene in two affected relatives with more severe disease (PMID: 10424815); This variant is associated with the following publications: (PMID: 28193612, 12601548, 31447099, 12707239, 24093860, 27532257, 18761664, 20031583, 31513939, 32009526, 34542152, 10424815) - |
Hypertrophic cardiomyopathy 4 Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1999 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 25, 2018 | This c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene has been reported in multiple hypertrophic cardiomyopathy (HMC) patients [PMID: 7786104, 10424815, 12707239] while observed with extremely low allele frequency in general population according to gnomad database. It has been demonstrated that this variant was co-segregated with disease in a HCM family [PMID: 10424815]. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene is classified as pathogenic. - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 08, 2022 | - - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 15, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2022 | The p.E1096* pathogenic mutation (also known as c.3286G>T), located in coding exon 30 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3286. This changes the amino acid from a glutamic acid to a stop codon within coding exon 30. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (Richard P et al. J. Med. Genet., 1999 Jul;36:542-5; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at