chr11-47338649-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000256.3(MYBPC3):c.2179G>A(p.Val727Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000614 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V727L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2179G>A | p.Val727Met | missense_variant | 23/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2179G>A | p.Val727Met | missense_variant | 23/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2179G>A | p.Val727Met | missense_variant | 22/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.2179G>A | p.Val727Met | missense_variant, NMD_transcript_variant | 23/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000605 AC: 15AN: 247856Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134594
GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461382Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 726972
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2023 | Identified independently and in conjunction with additional cardiogenetic variants in individuals with cardiomyopathy in published literature (Lopes et al., 2015; Burns et al., 2017; Helmes et al., 2020) and in individuals referred for cardiomyopathy genetic testing at GeneDx, but segregation data is limited or absent at this time; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24755471, 25351510, 32841044, 28790153, 31376648) - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 11, 2017 | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces valine with methionine at codon 727 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 28790153). One of these individuals carried a pathogenic variant in the same gene, which could explain the observed phenotype (PMID: 28790153). This variant has been identified in 19/279250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 727 of the MYBPC3 protein (p.Val727Met). This variant is present in population databases (rs564378953, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 28790153). This missense change has been observed to co-occur in individuals with a different variant in MYBPC3 that has been determined to be pathogenic (PMID: 25351510, 28790153), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 180964). 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. 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 08, 2023 | This missense variant replaces valine with methionine at codon 727 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 28790153, 32841044). One of these individuals also carried a different pathogenic missense variant in the same gene (PMID: 28790153). This variant has been identified in 19/279250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2022 | The p.V727M variant (also known as c.2179G>A), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2179. The valine at codon 727 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405). This alteration was also described in an HCM patient who had a second alteration in MYBPC3; however, the phase was unknown (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:). This alteration was also reported in a suspected drug-induced arrhythmia/sudden unexplained death cohort (Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at