chr11-47339358-G-GT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2113dupA(p.Thr705AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 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.2113dupA | p.Thr705AsnfsTer3 | frameshift_variant | Exon 22 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2113dupA | p.Thr705AsnfsTer3 | frameshift_variant | Exon 21 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.2113dupA | non_coding_transcript_exon_variant | Exon 22 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249266Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135222
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461696Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727132
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. Truncating variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This sequence change inserts 1 nucleotide in exon 22 of the MYBPC3 mRNA (c.2113dupA), causing a frameshift at codon 705. This creates a premature translational stop signal (p.Thr705Asnfs*3) and is expected to result in an absent or disrupted protein product. -
The Thr705fs variant has not been reported in the literature. This variant is p redicted to cause a frameshift, which alters the protein's amino acid sequence b eginning at codon 705 and leads to a premature stop codon two amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protei n. Loss of function is an established mechanism of disease for the MYBPC3 gene, which makes it highly likely that the Thr705fs variant is pathogenic. -
not provided Pathogenic:1
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: 22267749, 25524337, 27532257, 18533079) -
Cardiovascular phenotype Pathogenic:1
The c.2113dupA pathogenic mutation, located in coding exon 22 of the MYBPC3 gene, results from a duplication of A at nucleotide position 2113, causing a translational frameshift with a predicted alternate stop codon (p.T705Nfs*3). This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; 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