ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7630A>G (p.Thr2544Ala) (rs786202548)

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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 RCV000165409 SCV000216136 uncertain significance Hereditary cancer-predisposing syndrome 2014-08-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000681135 SCV000808593 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7630A>G at the cDNA level, p.Thr2544Ala (T2544A) 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 Thr2544Ala was not observed in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Thr2544Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000693796 SCV000821679 uncertain significance Neurofibromatosis, type 1 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 2544 of the NF1 protein (p.Thr2544Ala). 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: 185904). 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"). 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.

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