Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002317220 | SCV000670488 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2018-02-28 | criteria provided, single submitter | clinical testing | The p.K1436R variant (also known as c.4307A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4307. The lysine at codon 1436 is replaced by arginine, an amino acid with highly similar properties. Functional studies have shown this variant to have altered binding affinity and significant reduction in catalytic activity (Ahmadian MR et al. J. Mol. Biol. 2003 Jun;329:699-710). Based on internal structural analysis, this variant is anticipated to result in disruption of a known structural motif (Scheffzek K et al. EMBO J. 1998 Aug;17:4313-27). While this exact alteration has not been previously reported, two other alterations at the same codon (p.K1436E and p.K1436Q) have been reported in individuals diagnosed with NF1 (Thomas L et al. Hum. Mutat. 2012 Dec;33:1687-96; Valero MC et al. J Mol Diagn. 2011 Mar;13:113-22; Sabbagh A et al. Hum. Mutat. 2013 Nov;34:1510-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV001324279 | SCV001515228 | likely pathogenic | Neurofibromatosis, type 1 | 2023-08-16 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1436 of the NF1 protein (p.Lys1436Arg). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Lys1436 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21354044, 23913538, 24789688). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects NF1 function (PMID: 8628317, 12787671). 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. ClinVar contains an entry for this variant (Variation ID: 484060). This variant has not been reported in the literature in individuals affected with NF1-related conditions. |