ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2189A>C (p.Asn730Thr) (rs778033578)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538798 SCV000628416 uncertain significance Neurofibromatosis, type 1 2019-07-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 730 of the NF1 protein (p.Asn730Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs778033578, ExAC 0.003%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 457568). 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.
Ambry Genetics RCV000573213 SCV000670335 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-28 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001199898 SCV001370654 uncertain significance not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: NF1 c.2189A>C (p.Asn730Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251058 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2189A>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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