Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000211752 | SCV000061618 | pathogenic | Cardio-facio-cutaneous syndrome | 2012-06-26 | criteria provided, single submitter | clinical testing | The Thr241Pro variant in BRAF has been reported in the literature in four indivi duals with clinical features of Cardio-facio-cutaneous syndrome, LEOPARD, or Cos tello syndrome (Nava 2007, Schulz 2008, Sarkozy 2009). This variant was reported to have occurred de novo in three of those individuals. Therefore, this variant meets our criteria to be classified as pathogenic. |
Molecular Diagnostics Lab, |
RCV000207516 | SCV000263060 | likely pathogenic | not provided | 2015-07-23 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000515363 | SCV000611251 | pathogenic | Cardiofaciocutaneous syndrome 1; Lung carcinoma; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 | 2017-05-18 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000654966 | SCV000776876 | pathogenic | RASopathy | 2021-04-16 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 241 of the BRAF protein (p.Thr241Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant has been observed in individual(s) with cardio–facio–cutaneous syndrome (PMID: 17704260, 18042262). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29807). 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. Experimental studies have shown that this missense change affects BRAF protein function (PMID: 28404629). This variant disrupts the p.The241Met amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19206169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Blueprint Genetics | RCV000207516 | SCV000927223 | pathogenic | not provided | 2017-04-07 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000211752 | SCV002500556 | pathogenic | Cardio-facio-cutaneous syndrome | 2022-03-21 | criteria provided, single submitter | clinical testing | Variant summary: BRAF c.721A>C (p.Thr241Pro) results in a non-conservative amino acid change located in the Cysteine-rich (CRD) domain (Sarkozy_2009) 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 248524 control chromosomes. c.721A>C has been reported in the literature as a sporadic/de-novo variant in individuals affected with Cardiofaciocutaneous Syndrome/Leopard Syndrome (example, Nava_2007, Schulz_2008, Sarkozy_2009, Sekiguchi_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a moderate level of activation as measured by NIH-3T3 colony focus formation and a moderate increase in MEK and ERK phosphorylation in-vitro (example, Sarkozy_2009). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
MGZ Medical Genetics Center | RCV002288517 | SCV002579800 | pathogenic | Noonan syndrome 7 | 2022-01-11 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000022680 | SCV000043969 | pathogenic | Cardiofaciocutaneous syndrome 1 | 2009-04-01 | no assertion criteria provided | literature only | |
OMIM | RCV000022681 | SCV000043970 | pathogenic | LEOPARD syndrome 3 | 2009-04-01 | no assertion criteria provided | literature only | |
Gene |
RCV000055896 | SCV000086904 | not provided | Noonan syndrome with multiple lentigines | no assertion provided | literature only | ||
Genome |
RCV001089761 | SCV001245255 | not provided | Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 | no assertion provided | phenotyping only | Variant interpreted as Pathogenic and reported on 08-30-2016 by Lab Fulgent Genetics. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. |