ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.173T>G (p.Leu58Arg)

dbSNP: rs1597626094
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377684 SCV001575077 likely pathogenic Neurofibromatosis, type 1 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 58 of the NF1 protein (p.Leu58Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. This variant has been observed in individual(s) with neurofibromatosis type 1 (Invitae). This variant is not present in population databases (ExAC no frequency).
Ambry Genetics RCV003169936 SCV003893324 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-01-05 criteria provided, single submitter clinical testing The p.L58R variant (also known as c.173T>G), located in coding exon 2 of the NF1 gene, results from a T to G substitution at nucleotide position 173. The leucine at codon 58 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in at multiple individuals with a personal and/or family history that is consistent with NF1-related disease (Ambry internal data; van Minkelen R et al. Clin Genet, 2014 Apr;85:318-27). Additionally, structural analysis demonstrates that this alteration is disruptive to the N-terminal HEAT repeat domain (Ambry internal data; Naschberger A et al. Nature, 2021 Nov;599:315-319; Lupton CJ et al. Nat Struct Mol Biol, 2021 Dec;28:982-988; Chaker-Margot M et al. Mol Cell, 2022 Apr;82:1288-1296.e5; Sherekar M et al. J Biol Chem, 2020 Jan;295:1105-1119). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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