Submissions for variant NM_001042492.3(NF1):c.5768C>A (p.Thr1923Lys)

dbSNP: rs786203824

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216311	SCV001388101	pathogenic	Neurofibromatosis, type 1	2022-06-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1902 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25074460; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 945629). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1902 of the NF1 protein (p.Thr1902Lys).
GeneDx	RCV001556301	SCV001777859	uncertain significance	not provided	2019-04-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001216311	SCV002560909	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348720	SCV002649582	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-04-06	criteria provided, single submitter	clinical testing	The p.T1902K variant (also known as c.5705C>A), located in coding exon 38 of the NF1 gene, results from a C to A substitution at nucleotide position 5705. The threonine at codon 1902 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Ambry internal data; Garibotto F et al. Front Oncol, 2020 Jun;10:795). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.