Submissions for variant NM_001042492.3(NF1):c.4219A>G (p.Ser1407Gly)

dbSNP: rs587781755

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129962	SCV000184786	uncertain significance	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing	The p.S1407G variant (also known as c.4219A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4219. The serine at codon 1407 is replaced by glycine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. <span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort.<span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico<span style="background-color:initial"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.S1407G remains unclear.
Invitae	RCV000233760	SCV000284454	uncertain significance	Neurofibromatosis, type 1	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1386 of the NF1 protein (p.Ser1386Gly). This variant is present in population databases (rs587781755, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141448). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000480614	SCV000571928	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with severe bilateral ventriculomegaly, aqueductal stenosis, gray matter heterotopia, and polyhydramnios (Tolusso et al., 2021); Observed in cases and controls in a breast cancer case-control study (Dorling et al., 2021); Also known as 4219A>G; This variant is associated with the following publications: (PMID: 25486365, 22807134, 33442022, 33471991)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000233760	SCV001366315	uncertain significance	Neurofibromatosis, type 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3.
Genetic Services Laboratory, University of Chicago	RCV001818308	SCV002070585	uncertain significance	not specified	2020-10-07	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.4156A>G, in exon 31 that results in an amino acid change, p.Ser1386Gly. This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.00040% (dbSNP rs587781755). The p.Ser1386Gly change affects a highly conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser1386Gly substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1386Gly change remains unknown at this time.
Sema4, Sema4	RCV000129962	SCV002527558	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000233760	SCV002560393	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483261	SCV002786240	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-11-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467127	SCV004198337	uncertain significance	Juvenile myelomonocytic leukemia	2023-08-30	criteria provided, single submitter	clinical testing