Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002273187 | SCV002557886 | pathogenic | Neurofibromatosis, type 1 | 2022-02-02 | 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 with neurofibromatosis type 1 (NF1; MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more severely affected than the carrier parent (PMID: 20301288). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies show that this variant results in aberrant splicing due to usage of a cryptic site 4 nucleotides upstream of the canonical 3' splice site of intron 7, which is predicted to lead to a frameshift and generation of a premature stop codon, p.(Glu244Glyfs*9). These transcripts are predicted to be targeted by nonsense mediated decay (NMD). It was also reported that this variant induces complete mis-splicing of all mRNA arising from this allele, with undetectable levels of remnant normal splicing (Prof. S. Cooper, Splicing Diagnostics, Kid's Neuroscience Centre). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same splice site, is present in gnomAD (v3; 1 heterozygote, 0 homozygotes). 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). In addition, a different splice variant at this nucleotide position, c.731-5T>C, has been recorded in ClinVar as a VUS and likely benign, but no RNA studies have been performed. (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed; Peter MacCallum Cancer Centre report). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |