chr11-47347668-TC-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):βc.833delGβ(p.Gly278GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,573,808 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (β β ). 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 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.833delG | p.Gly278GlufsTer22 | frameshift_variant | Exon 8 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.833delG | p.Gly278GlufsTer22 | frameshift_variant | Exon 8 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.833delG | non_coding_transcript_exon_variant | Exon 8 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151924Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000107 AC: 2AN: 186304Hom.: 0 AF XY: 0.0000100 AC XY: 1AN XY: 100050
GnomAD4 exome AF: 0.00000352 AC: 5AN: 1421884Hom.: 0 Cov.: 33 AF XY: 0.00000284 AC XY: 2AN XY: 703588
GnomAD4 genome AF: 0.0000197 AC: 3AN: 151924Hom.: 1 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74212
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:6
This sequence change creates a premature translational stop signal (p.Gly278Glufs*22) 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 (rs727503212, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 164140). For these reasons, this variant has been classified as Pathogenic. -
The c.833del (p.Gly278Glufs*22) variant in the MYBPC3 gene is predicted to introduce a premature translation termination codon. This variant is rare in the general population database, gnomAD (2/181670). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant is reported in ClinVar (ID: 164140). Therefore, the c.833del (p.Gly278Glufs*22) variant in the MYBPC3 gene is classified as pathogenic. -
This variant has been identified in 1 HCM proband as part of our research program. The variant also segregated to an affected third-degree family member (3 meiosis). For further information please feel free to contact us. -
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The Gly278fs variant in MYBPC3 has not been reported in individuals with cardiom yopathy. Data from large population studies is insufficient to assess the freque ncy of this variant. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 278 and lead to a premature terminati on codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in MYBPC3 are established as pathogenic for HCM. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact of the variant. -
This variant deletes 1 nucleotide in exon 8 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 one individual affected with hypertrophic cardiomyopathy (PMID: 30282064) and in one individual affected with sudden cardiac death due to hypertrophic cardiomyopathy (PMID: 34135346). It has also been reported in one asymptomatic individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been identified in 2/186304 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
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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.Gly278GlufsX22 Upon initial review, we considered this variant very likely disease causing, given that there is strong evidence that frameshift variants in MYBPC3 cause cardiomyopathy. This variant has not been reported in published literature (as of 1/27/2012), however it is very likely to cause disease because the deletion of the Guanine nucleotide at position 833 causes a shift in the reading frame, changing the amino acid sequence and creating a premature stop codon. This would be predicted to either lead to a truncated protein or a no protein production due to nonsense-mediate mRNA decay. Both protein truncating and null variants in MYBPC3 have been associated with cardiomyopathy. This variant is not listed in dbSNP or 1000 genomes (as of 1/27/2012). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~4,700 Caucasian and African American individuals (as of 1/27/2012). However, a missense variant at that same codon is present in 1/3308 Caucasians and 47/1629 African-Americans. Given these data, we think it is likely that this variant causes cardiomyopathy. -
Not observed at a 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: 24793961, 27532257, 30282064, 31447099, 33673806, 34135346) -
Hypertrophic cardiomyopathy 4 Pathogenic:3
ACMG codes:PVS1; PS4M; PM2; PP5 -
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Cardiomyopathy Pathogenic:2
This variant deletes 1 nucleotide in exon 8 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30282064), in an individual affected with sudden cardiac death due to hypertrophic cardiomyopathy (PMID: 34135346), as well as in an asymptomatic individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been identified in 2/186304 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. -
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Left ventricular noncompaction 10 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The c.833delG pathogenic mutation, located in coding exon 8 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 833, causing a translational frameshift with a predicted alternate stop codon (p.G278Efs*22). This mutation has been reported in an individual with hypertrophic cardiomyopathy (HCM) and in HCM cohorts (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at