Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000168155 | SCV000218816 | pathogenic | Neurofibromatosis, type 1 | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1426 of the NF1 protein (p.Gln1426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 23047742; Invitae). ClinVar contains an entry for this variant (Variation ID: 188220). 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 NF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NF1 function (PMID: 8437860, 17114577). This variant disrupts the p.Gln1426 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23913538, 26969325; Invitae). 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. |
| Baylor Genetics | RCV003468826 | SCV004190778 | pathogenic | Juvenile myelomonocytic leukemia | 2022-11-15 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000168155 | SCV005085982 | pathogenic | Neurofibromatosis, type 1 | 2023-12-21 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated juvenile myelomonocytic leukemia (MIM#607785), familial spinal neurofibromatosis (MIM#162210), neurofibromatosis, type 1 (MIM#162200), neurofibromatosis-Noonan syndrome (MIM#601321) and Watson syndrome (MIM#193520). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GTPase-activator protein for Ras-like GTPase (RasGAP) domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. The p.(Gln1447Glu), p.(Gln1447Lys), p.(Gln1447Pro) and p.(Gln1447His) variants have been classified as likely pathogenic and pathogenic by at least ten multiple clinical diagnostic laboratories (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified once as pathogenic by a clinical diagnostic laboratory and has been reported in one individual with a clinical diagnosis of suspected neurofibromatosis, type 1 (ClinVar; PMID: 34860164). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |