ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3447G>A (p.Met1149Ile) (rs1064794277)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000632422 SCV000781985 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000485269 SCV000568606 likely pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing This variant is denoted NF1 c.3447G>A at the cDNA level, p.Met1149Ile (M1149I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed as a de novo finding in one individual with a clinical diagnosis of Neurofibromatosis Type 1 and was not identified in greater than 200 normal chromosomes evaluated (Griffiths 2007). NF1 Met1149Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. NF1 Met1149Ile occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider NF1 Met1149Ile to be a likely pathogenic variant.
Invitae RCV000632422 SCV000753602 likely pathogenic Neurofibromatosis, type 1 2018-04-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1149 of the NF1 protein (p.Met1149Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to several individuals affected with neurofibromatosis type 1, being found to be de novo in one case (PMID: 16944272, 27322474). ClinVar contains an entry for this variant (Variation ID: 420079). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different variant (c.3447G>T) giving rise to the same protein effect observed here (p.Met1149Ile) has been determined to be pathogenic (Invitae), indicating that this residue may be critical for protein function.. 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.

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