11-47337544-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000256.3(MYBPC3):āc.2449C>Gā(p.Arg817Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2449C>G | p.Arg817Gly | missense_variant | Exon 25 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2449C>G | p.Arg817Gly | missense_variant | Exon 24 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.2414-33C>G | intron_variant | Intron 24 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461692Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727128
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1
An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 817 of the MYBPC3 protein (p.Arg817Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27600940, 27618852, 28790153, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 810770). This variant disrupts the p.Arg817 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26914223, 27532257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Cardiomyopathy Uncertain:1
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Hypertrophic cardiomyopathy 4 Uncertain:1
This MYBPC3 Arg817Gly variant has been reported twice before in HCM probands (Galati , et al., 2016; Cecconi M, et al., 2016). This variant is rare and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified the variant in a HCM proband of Middle Eastern decent who was diagnosed in childhood and harbours 2 other variants: MYBPC3 Ala693Val & MYH7 Arg787His (Burns et al., 2019). Computational tools SIFT, MutationTaster, PolyPhen-HCM and PolyPhen-2 predict this variant to have a deleterious effect. A different amino acid change at the same protein position (p.Arg817Gln) has been reported in HCM probands (SCV000059139.4), suggesting that an amino acid substitution at this site may not be tolerated. In summary, based on this evidence we classify MYBPC3 Arg817Gly as a variant of "uncertain significance". -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at