rs369205562
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000256.3(MYBPC3):c.131G>A(p.Arg44His) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,609,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R44C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.131G>A | p.Arg44His | missense_variant | 2/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.131G>A | p.Arg44His | missense_variant | 2/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.131G>A | p.Arg44His | missense_variant | 2/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.131G>A | p.Arg44His | missense_variant, NMD_transcript_variant | 2/27 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000540 AC: 13AN: 240554Hom.: 0 AF XY: 0.0000762 AC XY: 10AN XY: 131156
GnomAD4 exome AF: 0.0000247 AC: 36AN: 1457318Hom.: 0 Cov.: 35 AF XY: 0.0000262 AC XY: 19AN XY: 724742
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74376
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 44 of the MYBPC3 protein (p.Arg44His). This variant is present in population databases (rs369205562, gnomAD 0.007%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30871747). ClinVar contains an entry for this variant (Variation ID: 180984). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYBPC3 function (PMID: 34097875). 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 histidine at codon 44 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). A functional study has reported that this variant may cause a slight change in protein stability but the impact was not as pronounced as that induced by a pathogenic variant (PMID: 34097875). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has been identified in 14/271948 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2023 | This missense variant replaces arginine with histidine at codon 44 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). A functional study has reported that this variant may cause a slight change in protein stability but the impact was not as pronounced as that induced by a pathogenic variant (PMID: 34097875). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has been identified in 14/271948 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2020 | Reported in an individual with DCM and atrial fibrillation; however, this proband was found to harbor a second cardiogenetic variant (Sousa et al. 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 180984; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30871747) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2022 | The p.R44H variant (also known as c.131G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 131. The arginine at codon 44 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Sousa A et al. Rev Port Cardiol (Engl Ed), 2019 Feb;38:129-139). 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