Submissions for variant NM_001042492.3(NF1):c.965T>C (p.Ile322Thr)

dbSNP: rs1417994243

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561475	SCV000663105	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-24	criteria provided, single submitter	clinical testing	The p.I322T variant (also known as c.965T>C), located in coding exon 9 of the NF1 gene, results from a T to C substitution at nucleotide position 965. The isoleucine at codon 322 is replaced by threonine, an amino acid with 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 6503 samples (13006 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, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of this alterationremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690184	SCV000817863	uncertain significance	Neurofibromatosis, type 1	2024-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 322 of the NF1 protein (p.Ile322Thr). This variant is present in population databases (no rsID available, 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: 480101). 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) has been performed 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757558	SCV000885835	uncertain significance	not provided	2017-08-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000690184	SCV002561854	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470833	SCV004198290	uncertain significance	Juvenile myelomonocytic leukemia	2023-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559231	SCV005048691	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-10	criteria provided, single submitter	clinical testing	The c.965T>C (p.I322T) alteration is located in exon 9 (coding exon 9) of the NF1 gene. This alteration results from a T to C substitution at nucleotide position 965, causing the isoleucine (I) at amino acid position 322 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005018964	SCV005647003	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-03-19	criteria provided, single submitter	clinical testing