Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000521124 | SCV000616393 | likely pathogenic | RASopathy | 2017-04-03 | reviewed by expert panel | curation | The c.1595G>A (p.Cys532Tyr) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; Partners LMM, GeneDx, EGL internal data; GTR ID's: 21766, 26957, 500060; SCV000112809.7, SCV000057229.13, SCV000197143.4). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Cys532Tyr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PP2, PP3. |
Gene |
RCV000080902 | SCV000057229 | likely pathogenic | not provided | 2024-07-03 | criteria provided, single submitter | clinical testing | Reported in two individuals with neurodevelopmental disorders from large cohort studies, including one individual in which the variant occurred de novo, but detailed clinical information was not provided on these individuals (PMID: 31785789, 33004838); Reported in an abstract by Spencer et al. (2016) in an individual with features of cardio-facio-cutaneous syndrome, but familial segregation information was not provided Spencer et al. (2016) British Journal of Dermatology. 174:e24e31; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 27478437, 29493581, 33004838, 31785789, 33057194, 35982159) |
Eurofins Ntd Llc |
RCV000080902 | SCV000112809 | likely pathogenic | not provided | 2017-08-29 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000150205 | SCV000197143 | likely pathogenic | Cardio-facio-cutaneous syndrome | 2017-07-28 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Labcorp Genetics |
RCV000521124 | SCV000659072 | likely pathogenic | RASopathy | 2022-05-13 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 532 of the BRAF protein (p.Cys532Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 31785789; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40380). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |