ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2968A>C (p.Thr990Pro)

gnomAD frequency: 0.00001  dbSNP: rs876658299
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219343 SCV000273339 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-07 criteria provided, single submitter clinical testing The p.T990P variant (also known as c.2968A>C), located in coding exon 22 of the NF1 gene, results from an A to C substitution at nucleotide position 2968. The threonine at codon 990 is replaced by proline, 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 6500 samples (13000 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.T990P remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000707267 SCV000836357 uncertain significance Neurofibromatosis, type 1 2021-02-12 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 229956). This sequence change replaces threonine with proline at codon 990 of the NF1 protein (p.Thr990Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline.
Genome-Nilou Lab RCV000707267 SCV002560245 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV003165553 SCV003896971 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-03-01 criteria provided, single submitter clinical testing The p.T990P variant (also known as c.2968A>C), located in coding exon 22 of the NF1 gene, results from an A to C substitution at nucleotide position 2968. The threonine at codon 990 is replaced by proline, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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