Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000497046 | SCV003461901 | pathogenic | Neurofibromatosis, type 1 | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp561*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with NF1-related conditions (PMID: 28961165, 30530636, 31776437). ClinVar contains an entry for this variant (Variation ID: 431596). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000497046 | SCV005400586 | pathogenic | Neurofibromatosis, type 1 | 2024-10-11 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, 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 (PMID: 20301288). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice in ClinVar as pathogenic by clinical laboratories. This variant, and a single base deletion with the same protein outcome, c.1683del; p.(Trp561*), have been observed in individuals diagnosed with neurofibromatosis type 1 (NF1)(PMID: 31776437). Another variant with the same protein outcome, c.1682G>A; p.(Trp561*) has been reported once as pathogenic in ClinVar, and has been observed in an individual with NF1 (PMID: 27838393). (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 |
| Medical Genetics, |
RCV000497046 | SCV000588732 | pathogenic | Neurofibromatosis, type 1 | 2017-02-02 | no assertion criteria provided | clinical testing |