Submissions for variant NM_001042492.3(NF1):c.2990G>A (p.Arg997Lys)

dbSNP: rs1555614462

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810271	SCV000950464	likely pathogenic	Neurofibromatosis, type 1	2018-07-23	criteria provided, single submitter	clinical testing	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). Experimental studies have shown that this nucleotide change can result in skipping of exon 22. Exon 22 is also known as exon 17 in the literature (PMID: 23913538). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with neurofibromatosis type 1 (PMID: 23913538, 29673180, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 997 of the NF1 protein (p.Arg997Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 22 of the NF1 coding sequence, which is part of the consensus splice site for this exon.
Ambry Genetics	RCV002345833	SCV001178976	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-05-07	criteria provided, single submitter	clinical testing	The c.2990G>A pathogenic mutation (also known as p.R997K), located in coding exon 22 of the NF1 gene, results from a G to A substitution at nucleotide position 2990. The amino acid change results in arginine to lysine at codon 997, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 22, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in a French NF1 cohort and is reported to result in exon skipping (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, a slight weakening in the native splice donor site efficiency and a weakening in the native splice donor site efficiency are predicted, respectively. Based on the available evidence, this variant is classified as a pathogenic mutation. .
Genome-Nilou Lab	RCV000810271	SCV002561817	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467437	SCV004190747	likely pathogenic	Juvenile myelomonocytic leukemia	2023-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV004588277	SCV005079225	likely pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28068329, 25486365, 2121369, 29673180, 23913538, Kiraz_2023, 35121649)