Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Agnes Ginges Centre for Molecular Cardiology, |
RCV000201920 | SCV000256667 | uncertain significance | Hypertrophic cardiomyopathy 1 | 2015-07-03 | criteria provided, single submitter | research | This MYBPC3 Gly5Trp variant has not previously been reported in the general population or the literature. We have identified this variant in 1 HCM proband who also carries a second variant of uncertain significance in TNNT2 (Arg293Cys). This patient was diagnosed at 62 years and has a maximal wall thickness of 20mm. This variant is not present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational analyses (Polyphen2, CADD, SIFT, Grantham) support a potentially deleterious effect. More evidence and additional data is needed to confirm the role of this variant. Thus, we classify this variant as of "uncertain significance". |
Invitae | RCV001060982 | SCV001225704 | uncertain significance | Hypertrophic cardiomyopathy | 2019-03-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with tryptophan at codon 5 of the MYBPC3 protein (p.Gly5Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy, however this individual carried a likely pathogenic variant in a different gene (PMID: 28790153). ClinVar contains an entry for this variant (Variation ID: 217839). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). 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. 5 |
Color Diagnostics, |
RCV001804939 | SCV002051901 | uncertain significance | Cardiomyopathy | 2023-03-16 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with tryptophan at codon 5 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 at least one individual affected with hypertrophic cardiomyopathy (PMID: 28790153, 32841044). This variant has been identified in 1/231870 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. |
Molecular Genetics, |
RCV002225097 | SCV002503867 | uncertain significance | Hypertrophic cardiomyopathy 4 | 2022-04-22 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glycine with tryptophan at codon 5 of the MYBPC3 protein, p.(Gly5Trp). The glycine residue is weakly conserved (100 vertebrates, UCSC), and is not located in an annotated domain. There is a large physicochemical difference between glycine and tryptophan. The variant is present in a single individual in a large population cohort (rs201278114, 1/231,870 alleles, 0 homozygotes in gnomAD v2.1). The variant has been classified as a variant of uncertain significance (ClinVar ID: 217839), and has been identified in a case with hypertrophic cardiomyopathy with another variant in TNNT2 (PMID: 28790153). Multiple lines of computational evidence predict a benign effect for the missense substitution (4/5 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PM2. |
Fulgent Genetics, |
RCV002485331 | SCV002789694 | uncertain significance | Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 | 2021-07-26 | criteria provided, single submitter | clinical testing |