rs202147520
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000256.3(MYBPC3):βc.3742G>Aβ(p.Gly1248Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000781 in 1,613,616 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 (β β ).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3742G>A | p.Gly1248Arg | missense_variant | Exon 33 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.3742G>A | p.Gly1248Arg | missense_variant | Exon 32 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249120Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135168
GnomAD4 exome AF: 0.0000794 AC: 116AN: 1461378Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 726980
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:5
The p.Gly1248Arg variant in MYBPC3 has been reported in at least 2 individuals with DCM (Cuenca 2016, Forleo 2017), 2 individuals with unexplained sudden death (Christiansen 2016, Neubauer 2017), and 2 individuals with HCM, including 1 child who carried a splice variant in MYBPC3 (Hofman 2007, Morita 2008, Coto 2012, GΓ³mez 2017). However, the variant failed to segregate with DCM in 2 affected members of 1 family (Cuenca 2016). This variant has also been identified in 0.005% (6/111626) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202147520). Computational prediction tools suggest that the p.Gly1248Arg variant may impact the protein, though conservation analysis show 2 mammals (orangutan and elephant) carry an arginine (Arg) at position 1248, suggesting that this change may be tolerated. Splice prediction tools predict that this variant may create a novel 3' splice site, though in vitro functional studies do not support a splicing impact (Ito 2017). In summary, the clinical significance of the p.Gly1248Arg variant is uncertain. The ACMG/AMP Criteria applied: BS4. -
- -
Identified in patients with HCM, DCM, alcoholic cardiomyopathy, and sudden death; in one family with DCM, the variant did not segregate with disease in two affected family members (PMID: 29773157, 18403758, 17908752, 22765922, 27532257, 28356264, 26899768, 28750076, 30847666, 27650965, 28074886, 30696458, 33782553, 32009526); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 23299917, 25637381, 17908752, 22765922, 27650965, 28356264, 28750076, 28679633, 30847666, 32841044, 33190526, 30696458, 18403758, 29773157, 33782553, 26899768, 28074886, 32009526) -
- -
- -
Primary familial hypertrophic cardiomyopathy Uncertain:2
- -
- -
Hypertrophic cardiomyopathy Uncertain:2
This missense variant replaces glycine with arginine at codon 1248 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional mini-gene assay has shown that this variant may not cause aberrant splicing (PMID: 28679633). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 22765922, 27532257, 28356264, 30696458, 32841044, 33190526, 33495596, 33495597, ClinVar SCV000747929.1) including one individual who also carried a pathogenic variant in the MYBPC3 gene (PMID: 33190526). This variant has also been reported in three individuals affected with dilated cardiomyopathy (PMID: 26899768, 28750076, 30847666), in one individual affected with cardiomyopathy (PMID: 32009526), and in four young individuals affected with sudden cardiac death (PMID: 17908752, 27650965, 28074886, 37589201) including one carrying a pathogenic MYBPC3 splice variant (PMID: 17908752). This variant has been identified in 8/249120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1248 of the MYBPC3 protein (p.Gly1248Arg). This variant is present in population databases (rs202147520, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of MYBPC3-related conditions and/or hypertrophic cardiomyopathy (PMID: 17908752, 18403758, 22765922, 27532257, 30696458, 30847666, 32841044, 33495596, 37652022, 37937776). ClinVar contains an entry for this variant (Variation ID: 42739). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change does not affect mRNA splicing (PMID: 28679633). 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. -
not specified Uncertain:1
Variant summary: MYBPC3 c.3742G>A (p.Gly1248Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249620 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3742G>A has been reported in the literature in individuals affected with hypertrophic cardiomyopathy or dilated cardiomyopathy (Hofman_2007, Morita_2008, Coto_2012, Cuenca_2016, Walsh_2017, Gomez_2017, Forleo_2017, Ware_2018, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, one co-occurrence with another pathogenic variant has been reported (MYBPC3 c.2149-2delA; Hofman_2007), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiomyopathy Uncertain:1
This missense variant replaces glycine with arginine at codon 1248 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional mini-gene assay has shown that this variant may not cause aberrant splicing (PMID: 28679633). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 22765922, 27532257, 28356264, 30696458, 32841044, 33190526, 33495596, 33495597, ClinVar SCV000747929.1) including one individual who also carried a pathogenic variant in the MYBPC3 gene (PMID: 33190526). This variant has also been reported in three individuals affected with dilated cardiomyopathy (PMID: 26899768, 28750076, 30847666), in one individual affected with cardiomyopathy (PMID: 32009526), and in four young individuals affected with sudden cardiac death (PMID: 17908752, 27650965, 28074886, 37589201) including one carrying a pathogenic MYBPC3 splice variant (PMID: 17908752). This variant has been identified in 8/249120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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
- -
Cardiovascular phenotype Uncertain:1
The c.3742G>A (p.G1248R) alteration is located in exon 33 (coding exon 33) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 3742, causing the glycine (G) at amino acid position 1248 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at