Submissions for variant NM_001042492.3(NF1):c.1649T>C (p.Leu550Pro)

dbSNP: rs886052798

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000263054	SCV000401709	uncertain significance	Café-au-lait macules with pulmonary stenosis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000318328	SCV000401710	uncertain significance	Neurofibromatosis, type 1	2016-06-14	criteria provided, single submitter	clinical testing	The c.1649T>C (p.Leu550Pro) variant has been reported in two studies in which it was found in a heterozygous state in two patients with neurofibromatosis, type 1 (Sabbagh et al. 2013; Duat Rodriguez et al. 2015). The p.Leu550Pro variant was absent from four controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium, despite good coverage in the region, suggesting it is a rare variant. The Leu550 residue is highly conserved. The evidence for this variant is limited. The p.Leu550Pro variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for neurofibromatosis, type 1.
Illumina Laboratory Services, Illumina	RCV000354441	SCV000401711	uncertain significance	Neurofibromatosis, familial spinal	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000277617	SCV000401712	uncertain significance	Neurofibromatosis-Noonan syndrome	2016-06-14	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000318328	SCV002521466	likely pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NF1 related disorder (PMID: 23913538). The variant has been observed in at least two similarly affected unrelated individuals (PMID:23913538, 25541118). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000318328	SCV005837758	likely pathogenic	Neurofibromatosis, type 1	2024-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 550 of the NF1 protein (p.Leu550Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 23913538, 25541118, 33443663). ClinVar contains an entry for this variant (Variation ID: 322570). 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 with a positive predictive value of 95%. 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.