Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000033306 | SCV000057211 | pathogenic | not provided | 2012-12-17 | criteria provided, single submitter | clinical testing | The G469R missense mutation has not been reported as a germline mutation to our knowlege; however, a different mutation at this residue (G469E) has been described in patients with Cardio-Facio-Cutaneous (CFC) Syndrome (Niihori et al., 2006). The G469R mutation identified in the fetus has been reported previously as a somatic mutation in association with haematopoietic and lymphoid cancer (Catalogue of Somatic Mutations in Cancer). The G469R missense change is a non-conservative substitution with a neutral, non-polar Gly residue being replaced by a positively-charged Arg residue. The NHLBI ESP Exome Variant Server reports that G469R was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001778653 | SCV002014945 | likely pathogenic | Cardio-facio-cutaneous syndrome | 2021-10-17 | criteria provided, single submitter | clinical testing | Variant summary: BRAF c.1405G>C (p.Gly469Arg) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic 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 251420 control chromosomes. c.1405G>C has been widely reported in the literature as a somatic variant in a variety of cancers such as melanoma and in at-least one case of fetal autopsy findings of Cardiofaciocutaneous Syndrome (example, Terry_2014). In the fetal case, both parents denied having personal or family histories of genetic disorders, malformations, or other significant abnormalities. Therefore, although a de-novo etiology is likely, it was not unequivocally established by parental analysis as reported in this study. Furthermore, pathogenic/likely pathogenic variants in HRAS, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, SOS1, and exon 2 of SHOC2 were reportedly not identified. At least one publication reports experimental evidence evaluating an impact on protein function (Damm_2014). The most pronounced variant effect results in constitutive ERK phosphorylation and Egr2 transcription along with a decrease in the proprtion of B cells in BRAF-G469R mice, as compared with empty murine stem cell virus vector or BRAF-wild type mice. No clinical diagnostic laboratories have submitted germline clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000015004 | SCV000035260 | pathogenic | Non-Hodgkin lymphoma | 2003-11-17 | no assertion criteria provided | literature only |