Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1PM2_SupportingPP3_StrongPP5_Very_Strong
The NM_000256(MYBPC3):c.1624G>T(p.Glu542Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
NM_000256 stop_gained, splice_region
Verdict is Pathogenic. Variant got 21 ACMG points.
|MYBPC3||ENST00000545968.6 ||c.1624G>T||p.Glu542Ter||stop_gained, splice_region_variant||17/35||5||NM_000256.3||P2|
|MYBPC3||ENST00000399249.6 ||c.1624G>T||p.Glu542Ter||stop_gained, splice_region_variant||16/34||5||A2|
|MYBPC3||ENST00000544791.1 ||c.1624G>T||p.Glu542Ter||stop_gained, splice_region_variant, NMD_transcript_variant||17/27||5|
GnomAD3 genomesCov.: 33
Submissions by phenotype
|Pathogenic, criteria provided, single submitter||clinical testing||GeneDx||Sep 11, 2018||The E542X variant in the MYBPC3 gene has been reported previously in a cohort of HCM patients, however, no specific clinical details were provided (Lopes et al., 2015). E542X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Moreover, the E542X variant is not observed in large population cohorts (Lek et al., 2016). Finally, this variant was identified independently in a patient with HCM referred for genetic testing at GeneDx.In summary, E542X in the MYBPC3 gene is interpreted as a pathogenic variant. -|
|Pathogenic, criteria provided, single submitter||clinical testing||Invitae||Jul 18, 2021||This sequence change creates a premature translational stop signal (p.Glu542*) 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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 430571). 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. -|
Find out detailed SpliceAI scores and Pangolin per-transcript scores at