rs727503188
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3PP5
The NM_000256.3(MYBPC3):c.2449C>T(p.Arg817Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R817G) has been classified as Likely pathogenic.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2449C>T | p.Arg817Trp | missense_variant | 25/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2449C>T | p.Arg817Trp | missense_variant | 25/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2449C>T | p.Arg817Trp | missense_variant | 24/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.2414-33C>T | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249226Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135206
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461692Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727128
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Sep 21, 2022 | The MYBPC3 c.2449C>T variant is classified as VUS (PS4_Moderate, PM2, PP3) The MYBPC3 c.2449C>T variant is a single nucleotide change in exon 25/35 of the MYBPC3 gene, which is predicted to change the amino acid arginine at position 817 in the protein, to tryptophan. The variant has been reported in at least 6 probands with a clinical presentation of Hypertrophic cardiomyopathy (PS4_Moderate) (PMID#25351510, 28749478, 33782553). Other variants at this same amino acid have also been reported in individuals with HCM (p.Arg817Gln/Gly) (PMID#26914223, 3378553). This variant is absent from population databases (PM2), is reported in dbSNP (rs727503188), is reported as ?disease causing in HGMD (CM1516385) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar#164078). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has also been reported in a homozygous state in a foetus with hydrops fatalis. Parental testing was implied and indicated a 'lack of phenotype in carrier' however this was not confirmed with cardiac imaging (PubMed#28749478). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2024 | - - |
Left ventricular noncompaction 10 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2024 | - - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 817 of the MYBPC3 protein (p.Arg817Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with nonimmune hydrops fetalis and hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 28749478, 33782553, 36264615; Invitae). ClinVar contains an entry for this variant (Variation ID: 164078). 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 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). 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. - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 12, 2013 | proposed classification - variant undergoing re-assessment, contact laboratory - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2023 | Identified in association with HCM in published literature (Lopes et al., 2015; Walsh et al., 2017; Thompson et al., 2021); Reported to be homozygous in at least one fetus with nonimmune hydrops fatalis (Shamseldin et al., 2018); Identified in a patient with HCM and status-post heart transplant who also harbored a second pathogenic variant in the MYBPC3 gene (Nafissi et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 26914223, 28679633, 34428338, 33782553, 27532257, 34645488, 34515413, 28749478, 36136372) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at