rs1265723882
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000256.3(MYBPC3):āc.97A>Gā(p.Thr33Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,294 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T33I) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.97A>G | p.Thr33Ala | missense_variant | 2/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.97A>G | p.Thr33Ala | missense_variant | 2/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.97A>G | p.Thr33Ala | missense_variant | 2/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.97A>G | p.Thr33Ala | missense_variant, NMD_transcript_variant | 2/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457294Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 724654
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2017 | In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 21750094). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 33 of the MYBPC3 protein (p.Thr33Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2022 | The p.T33A variant (also known as c.97A>G), located in coding exon 2 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 97. The threonine at codon 33 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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