ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2072T>C (p.Leu691Pro)

dbSNP: rs1131691132
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492230 SCV000581363 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-17 criteria provided, single submitter clinical testing The p.L691P variant (also known as c.2072T>C), located in coding exon 18 of the NF1 gene, results from a T to C substitution at nucleotide position 2072. The leucine at codon 691 is replaced by proline, an amino acid with similar properties. The<span style="font-size:13.3333339691162px">p.L691R (also known asc.2072T>G) variant, which is located at the same nucleotide position as this variant, was found in two probands in the NF1 French database; however, clinical information was not provided for these individuals (Sabbagh A, Hum. Mutat. 2013 Nov; 34(11):1510-8.).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this acceptor/donor splice site; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV000705843 SCV000834860 likely pathogenic Neurofibromatosis, type 1 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 691 of the NF1 protein (p.Leu691Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 and/or NF1-related conditions (PMID: 31776437; Invitae). ClinVar contains an entry for this variant (Variation ID: 429016). 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 with a positive predictive value of 95%. 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.
GeneDx RCV001786393 SCV002028701 likely pathogenic not provided 2023-01-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23913538, 31776437, Kam and Yac-Kpeli[article], 25486365)
Ambry Genetics RCV003159595 SCV003897493 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-02-24 criteria provided, single submitter clinical testing The p.L691P variant (also known as c.2072T>C), located in coding exon 18 of the NF1 gene, results from a T to C substitution at nucleotide position 2072. The leucine at codon 691 is replaced by proline, an amino acid with similar properties. This alteration was identified in a cohort of 427 Korean patients with a confirmed or suspected clinical diagnosis of neurofibromatosis type 1 (Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This alteration has been observed in individuals with features of NF1-related disease (Ambry internal data). 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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