ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1264G>A (p.Ala422Thr) (rs786202145)

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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 RCV000164813 SCV000215496 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000681190 SCV000808648 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1264G>A at the cDNA level, p.Ala422Thr (A422T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a gastrointestinal tumor (Chong 2013). NF1 Ala422Thr was observed at an allele frequency of 0.0029% (1/34,414) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ala422Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000706979 SCV000836055 uncertain significance Neurofibromatosis, type 1 2018-05-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 422 of the NF1 protein (p.Ala422Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. 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: 185401). 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.

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