Submissions for variant NM_001042492.3(NF1):c.4357G>A (p.Val1453Ile)

gnomAD frequency: 0.00002  dbSNP: rs199474755

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214015	SCV000272997	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-07	criteria provided, single submitter	clinical testing	​<span style="background-color:initial">Thep.V1453I<span style="background-color:initial"> variant (also known as c.4357G>A), located in coding exon 33 of theNF1<span style="background-color:initial"> gene, results from a G to A substitution at nucleotide position 4357. The valine at codon 1453 is replaced by isoleucine, an amino acid with highly 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. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign yet deleterious by PolyPhen and SIFTin silico<span style="background-color:initial"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.V1453I remains unclear.
Invitae	RCV000234155	SCV000284457	uncertain significance	Neurofibromatosis, type 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1432 of the NF1 protein (p.Val1432Ile). This variant is present in population databases (rs199474755, gnomAD 0.004%). 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: 229695). 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) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. 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.
GeneKor MSA	RCV000214015	SCV000822097	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001815254	SCV002063597	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000234155	SCV002560412	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165549	SCV003897081	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-28	criteria provided, single submitter	clinical testing	The p.V1432I variant (also known as c.4294G>A), located in coding exon 32 of the NF1 gene, results from a G to A substitution at nucleotide position 4294. The valine at codon 1432 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001815254	SCV004021650	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; 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.; Observed in an individual with a personal or family history of breast and/or ovarian cancer (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 25486365, 22807134, 31159747, Martorana2022[CaseReport])
Medical Genetics, University of Parma	RCV000234155	SCV002567789	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	flagged submission	clinical testing