ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.730G>A (p.Glu244Lys)

dbSNP: rs1567826188
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000692867 SCV000820713 pathogenic Neurofibromatosis, type 1 2025-01-13 criteria provided, single submitter clinical testing This sequence change affects codon 244 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 18546366, 33876461, 33999308; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 571661). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 (also known as exon 5), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18546366, 33999308). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV001091252 SCV001247179 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Medical Genetics, University of Parma RCV000692867 SCV002567804 pathogenic Neurofibromatosis, type 1 2022-08-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001091252 SCV004222180 likely pathogenic not provided 2023-03-15 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individuals with neurofibromatosis 1 (NF1) (PMID: 18546366 (2008), 33999308 (2021)). Published splicing studies have shown that this variant results in aberrant NF1 splicing and causes truncated NF1 protein product (PMID: 18546366 (2018)). The variant has also been shown to result in reduced NF1 gene expression levels (PMID: 33999308 (2021)). Based on the available information, this variant is classified as likely pathogenic.

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