chr11-47338554-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000256.3(MYBPC3):c.2274C>T(p.Gly758Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2274C>T | p.Gly758Gly | synonymous_variant | Exon 23 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2274C>T | p.Gly758Gly | synonymous_variant | Exon 22 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.2274C>T | non_coding_transcript_exon_variant | Exon 23 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249212Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135200
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461688Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727128
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:3
The p.Gly758Gly variant in MYBPC3 has been reported in at least 2 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 2 affected relatives from one family (Bagnall 2018 PMID: 30025578, LMM Data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42609) and has been identified in 0.0015% (1/68016) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools predict a splicing impact, resulting from the creation of a novel 5' (donor) splice site. This is corroborated by an vitro splicing study on patient RNA from blood, which showed aberrant splicing on exon 23 that resulted in a protein that is truncated by 12 amino acids and not expected to affect the reading frame (Bagnall 2018 PMID: 30025578). It is unclear how this truncation would cause disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PP3, PM4. -
This sequence change affects codon 758 of the MYBPC3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 12 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs397515957, gnomAD no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30025578). ClinVar contains an entry for this variant (Variation ID: 42609). Studies have shown that this variant results in the activation of a cryptic splice site in exon 23 (PMID: 30025578). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
- -
MYBPC3 Gly758= has been previously reported in a HCM proband by another laboratory (LMM, ClinVar:SCV000059125) and is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband, and other affected relatives (Bagnall et al., 2018). Splice prediction tool MaxEntScan predicts that this variant will result in aberrant splicing. RNA extracted from the blood of all 3 affected individuals showed that this causes a new splice donor and aberrant splicing of exon 23, resulting in a 36 base pair in-frame truncation (Bagnall et al., 2018). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), causes a truncated protein (PM4), segregates to affected family members (PP1) and in silico tools predict aberrant splicing to occur (PP3), therefore we classify MYBPC3 Gly758= as 'likely pathogenic'. -
not provided Pathogenic:1
RNA analysis revealed exon 23 was truncated by 36 nucleotides, leading to an in-frame deletion of 12 amino acids (Gly758-Ile769) (Bagnall et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing.; Reported in ClinVar with conflicting classifications (ClinVar Variant ID# 42609; ClinVar); This variant is associated with the following publications: (PMID: 31243064, 30025578) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at