Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000540881 | SCV000628519 | pathogenic | Neurofibromatosis, type 1 | 2024-11-19 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1143 of the NF1 protein (p.His1143Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type I (PMID: 12807981, 18546366, 30530636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 457648). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 12807981, 30530636). For these reasons, this variant has been classified as Pathogenic. |
| Center for Human Genetics, |
RCV000540881 | SCV000781983 | likely pathogenic | Neurofibromatosis, type 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000540881 | SCV002559955 | likely pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002330834 | SCV002618972 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-07-07 | criteria provided, single submitter | clinical testing | The c.3427C>T variant (also known as p.H1143Y), located in coding exon 26 of the NF1 gene, results from a C to T substitution at nucleotide position 3427. The histidine at codon 1143 is replaced by tyrosine, an amino acid with similar properties. The variant has been detected in multiple individuals with neurofibromatosis type 1 (Ars E et al. J Med Genet, 2003 Jun;40:e82; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in partial skipping of exon 26 (Ars E et al. J Med Genet, 2003 Jun;40:e82; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |