rs397516049
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.436dupA(p.Thr146fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,560,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.424
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]
Genome browser will be placed here
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 11-47350082-G-GT is Pathogenic according to our data. Variant chr11-47350082-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 42751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.436dupA | p.Thr146fs | frameshift_variant | 4/35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.436dupA | p.Thr146fs | frameshift_variant | 4/34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.436dupA | non_coding_transcript_exon_variant | 4/27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
1
AN:
152196
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 7.10e-7 AC: 1AN: 1408112Hom.: 0 Cov.: 35 AF XY: 0.00000144 AC XY: 1AN XY: 695542
GnomAD4 exome
AF:
AC:
1
AN:
1408112
Hom.:
Cov.:
35
AF XY:
AC XY:
1
AN XY:
695542
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74352
GnomAD4 genome
AF:
AC:
1
AN:
152196
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74352
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Thr146Asnfs*7) 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). This variant is present in population databases (rs397516049, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42751). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 02, 2013 | The Thr146fs variant in MYBPC3 was identified in three individuals with HCM from two families by our laboratory. This frameshift variant is predicted to alter t he protein?s amino acid sequence beginning at position 146 and lead to a prematu re termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in the MYBPC3 gen e are established as pathogenic for HCM. In summary, this variant meets our crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon a bsence from controls and loss of function of the MYBPC3 gene. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 14, 2024 | This variant inserts 1 nucleotide in exon 4 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 26914223, 27532257, 30297972, 32228044, 32841044, 33495597, 34556856). This variant has been identified in 1/31388 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. - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 08, 2021 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2022 | Identified in patients with HCM referred for genetic testing at GeneDx and in the published literature (Alfares et al., 2015; Murphy et al., 2016; Walsh et al., 2017); also known as c.436_437insA due to alternate nomenclature; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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; This variant is associated with the following publications: (PMID: 27532257, 26914223, 25611685) - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 07, 2022 | Variant summary: MYBPC3 c.436dupA (p.Thr146AsnfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 167712 control chromosomes. c.436dupA has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Murphy_2016, Alfares_2015, Ho_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2022 | The c.436dupA pathogenic mutation, located in coding exon 4 of the MYBPC3 gene, results from a duplication of A at nucleotide position 436, causing a translational frameshift with a predicted alternate stop codon (p.T146Nfs*7). This alteration has been reported in hypertrophic cardiomyopathy (HCM) genetic testing cohorts; however, clinical details were limited (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; 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
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at