ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4399A>G (p.Thr1467Ala) (rs876660162)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218722 SCV000277355 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign)
Invitae RCV000476720 SCV000542024 uncertain significance Neurofibromatosis, type 1 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1467 of the NF1 protein (p.Thr1467Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 233057). 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. 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.
GeneDx RCV000681188 SCV000808646 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing This variant is denoted NF1 c.4399A>G at the cDNA level, p.Thr1467Ala (T1467A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Thr1467Ala was observed at an allele frequency of 0.003% (1/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Thomas 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Thr1467Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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