ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3104T>G (p.Met1035Arg) (rs137854553)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000000375 SCV000830686 likely pathogenic Neurofibromatosis, type 1 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 1035 of the NF1 protein (p.Met1035Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with neurofibromatosis type I (NF1) and Neurofibromatosis-Noonan syndrome (NFNS) (Invitae). It has also been reported to be de novo in an individual with Noonan syndrome with multiple lentigines (LEOPARD syndrome) (PMID: 8807336). ClinVar contains an entry for this variant (Variation ID: 347). 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: "Probably 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 individuals with NF1-related conditions (PMID: 9042399, 24789688, 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000000375 SCV000020519 pathogenic Neurofibromatosis, type 1 1996-01-01 no assertion criteria provided literature only

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