rs727504265
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2780_2781del(p.Thr927IlefsTer123) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T927T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2780_2781del | p.Thr927IlefsTer123 | frameshift_variant | 27/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2780_2781del | p.Thr927IlefsTer123 | frameshift_variant | 27/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2780_2781del | p.Thr927IlefsTer123 | frameshift_variant | 26/34 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460040Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726280
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2023 | Reported in unrelated individuals with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Zimmerman et al., 2010; Marsiglia et al., 2013; Alfares et al., 2015; Burns et al., 2017; Walsh et al., 2017); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 24093860, 25611685, 28790153, 28408708, 28615295, 33087929, 20474083) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 29, 2019 | The p.Thr927Ilefs*123 variant in MYBPC3 has been identified in at least 3 individuals with HCM and segregated with disease in 1 affected family member (Burns 2017, LMM data). It was absent from large population studies but has been reported in ClinVar (Variation ID #177660). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 927 and leads to a premature termination codon 123 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Thr927Ilefs*123) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177660). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 14, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 2023 | The c.2780_2781delCA pathogenic mutation, located in coding exon 27 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 2780 to 2781, causing a translational frameshift with a predicted alternate stop codon (p.T927Ifs*123). This mutation has been reported in individuals with hypertrophic cardiomyopathy, as well as in one dilated cardiomyopathy case, although clinical details were limited (Zimmerman RS et al. Genet. Med., 2010 May;12:268-78; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at