rs758421775
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_000256.3(MYBPC3):c.3109C>T(p.Arg1037Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,608,210 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. R1037H) 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.3109C>T | p.Arg1037Cys | missense_variant | 29/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3109C>T | p.Arg1037Cys | missense_variant | 29/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.3109C>T | p.Arg1037Cys | missense_variant | 28/34 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000816 AC: 2AN: 245164Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133474
GnomAD4 exome AF: 0.00000962 AC: 14AN: 1455956Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 724638
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74380
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1037 of the MYBPC3 protein (p.Arg1037Cys). 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 individual(s) with hypertrophic cardiomyopathy (PMID: 25132132). ClinVar contains an entry for this variant (Variation ID: 574286). 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 | Dec 13, 2023 | This missense variant replaces arginine with cysteine at codon 1037 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 25132132). This variant has not been identified 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2023 | This missense variant replaces arginine with cysteine at codon 1037 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 24865491, 25132132). One of these individuals also carried a second variant in the MuRF2 gene (PMID: 24865491). This variant has not been identified 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;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 13, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2022 | The p.R1037C variant (also known as c.3109C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3109. The arginine at codon 1037 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Su M et al. Int J Mol Sci, 2014 May;15:9302-13; Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7). This amino acid position is well 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