ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1658A>G (p.His553Arg) (rs1064794274)

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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 RCV000632424 SCV000781925 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000480683 SCV000568602 likely pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1658A>G at the cDNA level, p.His553Arg (H553R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has been observed in several individuals meeting diagnostic criteria for Neurofibromatosis I, with de novo occurrence reported in one individual (Griffiths 2007, Hölzel 2010, Calì 2016, Evans 2016). NF1 His553Arg 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 Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. NF1 His553Arg occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider NF1 His553Arg to be a likely pathogenic variant.
Invitae RCV000632424 SCV000753604 pathogenic Neurofibromatosis, type 1 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 553 of the NF1 protein (p.His553Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with neurofibromatosis type 1, being found to be de novo in one of them (PMID: 16944272, 27322474, 27838393). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 420076). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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