Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004799752 | SCV005422207 | uncertain significance | not specified | 2024-10-23 | criteria provided, single submitter | clinical testing | Variant summary: BRAF c.1722C>G (p.His574Gln) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1722C>G has been reported in the literature in at least an individual with seizures and intellectual disability (example: Pierpont_2022). This report does not provide unequivocal conclusions about association of the variant with Cardiofaciocutaneous Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35524774). ClinVar contains an entry for this variant (Variation ID: 40384). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV003539765 | SCV004307135 | uncertain significance | RASopathy | 2023-07-30 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects BRAF function (PMID: 27478040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 40384). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 574 of the BRAF protein (p.His574Gln). |
| 3billion | RCV000677114 | SCV002521799 | likely pathogenic | Cardiofaciocutaneous syndrome 1 | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040384). A different missense change at the same codon (p.His614Tyr) has been reported to be associated with BRAF related disorder (ClinVar ID: VCV000044810). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Ambry Genetics | RCV001265848 | SCV001444020 | likely pathogenic | Inborn genetic diseases | 2018-01-29 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV000677114 | SCV000803185 | pathogenic | Cardiofaciocutaneous syndrome 1 | 2018-05-22 | criteria provided, single submitter | research | |
| Gene |
RCV000033328 | SCV000057233 | pathogenic | not provided | 2023-10-06 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect with increased ERK phosphorylation (PMID: 27478040); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 27505666, 34625582, 27478437, 35353015, Luk2013[CaseReport], 27478040) |
| Service de Génétique Moléculaire, |
RCV000824924 | SCV000965956 | likely pathogenic | Cardio-facio-cutaneous syndrome | no assertion criteria provided | clinical testing |