ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3467A>G (p.Asn1156Ser) (rs199474764)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000793336 SCV000932684 pathogenic Neurofibromatosis, type 1 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1156 of the NF1 protein (p.Asn1156Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs199474764, ExAC 0.001%). This variant has been reported in several individuals affected with clinical features consistent with neurofibromatosis, type 1 (PMID: 10712197, 24789688), including at least one de novo observation (Invitae). ClinVar contains an entry for this variant (Variation ID: 68332). 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"). 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. This variant disrupts the p.Asn1156 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001314 SCV001158497 uncertain significance not specified 2019-05-22 criteria provided, single submitter clinical testing The NF1 c.3467A>G; p.Asn1156Ser variant (rs199474764) has been described in individuals affected with neurofibromatosis type 1 (NF1; Fahsold 2000, Xu 2014). It is observed on only one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 1156 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, computational splicing programs (Alamut v.2.11) predict that this variant impacts splicing by creating a cryptic splice acceptor site, and analysis of mRNA from peripheral blood of an individual harboring this variant demonstrated aberrant splicing leading to exon skipping (Xu 2014). However, this study did not quantify the amount of incorrectly spliced transcript. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. REFERNECES Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60.
UniProtKB/Swiss-Prot RCV000059184 SCV000090713 not provided not provided no assertion provided not provided

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