rs769167548
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000256.3(MYBPC3):c.640G>A(p.Asp214Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,606,640 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D214E) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.640G>A | p.Asp214Asn | missense_variant | 5/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.640G>A | p.Asp214Asn | missense_variant | 5/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.640G>A | p.Asp214Asn | missense_variant | 5/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.640G>A | p.Asp214Asn | missense_variant, NMD_transcript_variant | 5/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000290 AC: 7AN: 241606Hom.: 0 AF XY: 0.0000303 AC XY: 4AN XY: 131898
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1454394Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11AN XY: 723750
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with hypertrophic cardiomyopathy in published literature (Whiffin et al., 2017; Mademont-Soler et al., 2017); This variant is associated with the following publications: (PMID: 26582918, 23861362, 28771489, 33782553, 28518168) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 214 of the MYBPC3 protein (p.Asp214Asn). This variant is present in population databases (rs769167548, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28771489, 33782553). ClinVar contains an entry for this variant (Variation ID: 191705). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 31, 2023 | This missense variant replaces aspartic acid with asparagine at codon 214 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: 28771489, 33782553). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666); this individual also carried a pathogenic variant in the DSP gene that could explain the observed phenotype. This variant has been identified in 9/273006 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. - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | - | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2023 | This missense variant replaces aspartic acid with asparagine at codon 214 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: 28771489, 33782553). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666); this individual also carried a pathogenic variant in the DSP gene that could explain the observed phenotype. This variant has been identified in 9/273006 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 | Apr 21, 2023 | The p.D214N variant (also known as c.640G>A), located in coding exon 5 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 640. The aspartic acid at codon 214 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465). This alteration has also been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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