Submissions for variant NM_001042492.3(NF1):c.4328C>T (p.Ser1443Leu)

dbSNP: rs1555618566

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632429	SCV000753609	pathogenic	Neurofibromatosis, type 1	2024-10-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1422 of the NF1 protein (p.Ser1422Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis, type 1 (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 527535). 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%. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000632429	SCV000839148	uncertain significance	Neurofibromatosis, type 1	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001540502	SCV001758393	pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduction in RAS GAP activity and protein expression similar to wildtype (Douben H et al. (2023) Hindawi Human Mutation. 2023 (Article ID 9628049):1-14); 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: 21520333, 23656349, 36251260, 35264596, Douben2023[Functional study], 25486365, 22807134)
Ambry Genetics	RCV002331121	SCV002629944	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-03-10	criteria provided, single submitter	clinical testing	The p.S1422L variant (also known as c.4265C>T), located in coding exon 31 of the NF1 gene, results from a C to T substitution at nucleotide position 4265. The serine at codon 1422 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001540502	SCV005624595	likely pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	The NF1 c.4265C>T (p.Ser1422Leu) variant has been detected in individuals with neurofibromatosis 1 (PMID: 36251260 (2022) and Quest internal data). A published in vitro study indicated that this variant results in reduced RAS GAP activity relative to the wildtype without affecting protein expression (PMID: 36251260 (2022) and Douben H et al. (2023) Hindawi Human Mutation. 2023 (Article ID 9628049):1-14)). This variant has also been reported in an individual with breast cancer in the literature (PMID: 35264596 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.