ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3104T>C (p.Met1035Thr) (rs137854553)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523086 SCV000617579 uncertain significance not provided 2018-11-09 criteria provided, single submitter clinical testing The M1035T variant in the NF1 gene has been reported in an individual with a diagnosis or clinical suspicion of neurofibromatosis type 1; phenotypic information was otherwise not available on this individual (Xu et al., 2014). The M1035T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M1035T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is located in the GTPase activating protein domain (Xu et al., 1990; Luo et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret M1035T as a variant of uncertain significance.
Invitae RCV000497241 SCV000951363 uncertain significance Neurofibromatosis, type 1 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1035 of the NF1 protein (p.Met1035Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical diagnosis or suspicion of neurofibromatosis type 1 (PMID: 24789688, Invitae). ClinVar contains an entry for this variant (Variation ID: 431618). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Met1035 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in affected individuals (Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Medical Genetics, University of Parma RCV000497241 SCV000588757 uncertain significance Neurofibromatosis, type 1 2017-02-02 no assertion criteria provided clinical testing

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