Submissions for variant NM_001042492.3(NF1):c.2072T>C (p.Leu691Pro)

dbSNP: rs1131691132

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705843	SCV000834860	likely pathogenic	Neurofibromatosis, type 1	2025-01-08	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 691 of the NF1 protein (p.Leu691Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 and/or NF1-related conditions (PMID: 31776437; internal data). ClinVar contains an entry for this variant (Variation ID: 429016). 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) 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.
GeneDx	RCV001786393	SCV002028701	likely pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23913538, 31776437, Kam and Yac-Kpeli[article], 25486365)
Ambry Genetics	RCV003159595	SCV003897493	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-08-09	criteria provided, single submitter	clinical testing	The p.L691P variant (also known as c.2072T>C), located in coding exon 18 of the NF1 gene, results from a T to C substitution at nucleotide position 2072. The leucine at codon 691 is replaced by proline, an amino acid with similar properties. This alteration was identified in a cohort of 427 Korean patients with a confirmed or suspected clinical diagnosis of neurofibromatosis type 1 (Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This alteration has been observed in multiple individuals with features of NF1-related disease (Ambry internal data). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000705843	SCV005199957	likely pathogenic	Neurofibromatosis, type 1	2024-08-26	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000705843	SCV005416548	likely pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5_Supporting+PP3+PP2+PS4_Supporting+PP4