ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1900A>G (p.Ile634Val) (rs745906742)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467659 SCV000542166 uncertain significance Neurofibromatosis, type 1 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 634 of the NF1 protein (p.Ile634Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs745906742, ExAC 0.006%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 404567). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000570055 SCV000666656 likely benign Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
GeneDx RCV000681096 SCV000808552 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing The I634V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 5/111488 (0.0045%) alleles from individuals of European (non-Finnish) background, in the ExAC dataset (Lek et al., 2016). The I634V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. This variant is located within the GTPase activating protein domain (Luo et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.

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