Submissions for variant NM_001042492.3(NF1):c.7189G>A (p.Gly2397Arg)

dbSNP: rs1135402900

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics, University of Parma	RCV000497028	SCV000588832	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000497028	SCV001140394	pathogenic	Neurofibromatosis, type 1	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001840618	SCV002099598	likely pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30290804, 26056819, 28961165, 25486365)
Invitae	RCV000497028	SCV002115954	likely pathogenic	Neurofibromatosis, type 1	2021-04-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 2376 of the NF1 protein (p.Gly2376Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 47, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 28961165, 26056819, 30290804). This variant is also known as c.7189G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 431686).
Genome-Nilou Lab	RCV000497028	SCV002560559	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000497028	SCV002576436	likely pathogenic	Neurofibromatosis, type 1	2022-07-25	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1_MOD, PS4_MOD, PM5_SUP, PP4
Ambry Genetics	RCV002367673	SCV002662683	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-02	criteria provided, single submitter	clinical testing	The c.7126G>A pathogenic mutation (also known as p.G2376R), located in coding exon 47 of the NF1 gene, results from a G to A substitution at nucleotide position 7126. The amino acid change results in glycine to arginine at codon 2376, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 47, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This mutation has been reported in multiple individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Zhang J et al. Sci Rep, 2015 Jun;5:11291; Bonatti F et al. Int J Mol Sci, 2017 Sep;18:; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000497028	SCV002764806	pathogenic	Neurofibromatosis, type 1	2021-02-16	criteria provided, single submitter	clinical testing