ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2521A>C (p.Thr841Pro)

dbSNP: rs2067066952
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Medical Molecular Genetics Department, National Research Center RCV001172242 SCV000999064 likely pathogenic Neurofibromatosis, type 1 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001172242 SCV002953087 pathogenic Neurofibromatosis, type 1 2022-04-17 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 841 of the NF1 protein (p.Thr841Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 31717729). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 694508). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV003169088 SCV003861603 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-12-12 criteria provided, single submitter clinical testing The p.T841P variant (also known as c.2521A>C), located in coding exon 21 of the NF1 gene, results from an A to C substitution at nucleotide position 2521. The threonine at codon 841 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported as a de novo variant in two pediatric patients affected with neurofibromatosis type 1 (NF1) (Yao R et al. Genes (Basel), 2019 Oct;10:; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 Dec;9:e1631). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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