rs727503203
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1357_1358delCC(p.Pro453CysfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,270 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
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1357_1358delCC | p.Pro453CysfsTer21 | frameshift_variant | Exon 16 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.1357_1358delCC | p.Pro453CysfsTer21 | frameshift_variant | Exon 15 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.1357_1358delCC | non_coding_transcript_exon_variant | Exon 16 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000820 AC: 2AN: 243790Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132202
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459270Hom.: 0 AF XY: 0.00000276 AC XY: 2AN XY: 725700
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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; Reported in association with HCM (Waldmller et al., 2003; Walsh et al., 2017; Norrish et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31006259, 19574547, 27532257, 30731207, 12788380) -
PVS1, PM2, PP1 -
Hypertrophic cardiomyopathy Pathogenic:2
proposed classification - variant undergoing re-assessment, contact laboratory -
This sequence change creates a premature translational stop signal (p.Pro453Cysfs*21) 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 (rs727503203, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 12788380, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164118). For these reasons, this variant has been classified as Pathogenic. -
Cardiomyopathy Pathogenic:1
- -
Hypertrophic cardiomyopathy 4 Pathogenic:1
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000164118 / PMID: 12788380). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Cardiovascular phenotype Pathogenic:1
The c.1357_1358delCC pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of two nucleotides at positions 1357 to 1358, causing a translational frameshift with a predicted alternate stop codon (p.P453Cfs*21). In a hypertrophic cardiomyopathy (HCM) cohort, this alteration was previously described in two Indian families, who were distantly related by a common founder and exhibited variable expressivity and incomplete penetrance (Waldmüller S et al. J Mol Cell Cardiol. 2003;35:623-36). This alteration has also been reported in association with dilated cardiomyopathy (DCM) Daoud H et al. J Mol Diagn, 2019 05;21:437-448). 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