ClinVar Genomic variation as it relates to human health

PVS1, PS4, PM2

The p.R681* pathogenic mutation (also known as c.2041C>T), located in coding exon 18 of the NF1 gene, results from a C to T substitution at nucleotide position 2041. This changes the amino acid from an arginine to a stop codon within coding exon 18. This alteration has been identified in several individuals meeting NIH diagnostic criteria for neurofibromatosis type 1 (NF1) ( Ars E et al, Hum. Mol. Genet. 2000 Jan; Violante IR et al. Brain 2013 Mar;136(Pt 3):918-25 Maruoka R et al. Genet Test Mol Biomarkers, 2014 Nov;18:722-35; Zafar R et al. Radiol Case Rep, 2016 Mar;11:33-5; 9(2):237-47; Yao R et al. Genes (Basel), 2019 10;10:; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 12;9:e1631). In addition, several functional studies have shown that this mutation causes reduced protein expression and can contribute to the development of optic gliomas and neurofibromas (Li K et al. Dis Model Mech, 2016 Jul;9:759-67; Toonen JA et al. Hum. Mol. Genet., 2016 May;25:1703-13; Gutmann DH. Expert Rev Neurother, 2016 Sep;16:999-1001). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

A heterozygous nonsense variation in exon 18 of the NF1 gene that results in premature truncation of the Arginine at codon 681. The observed variant c.2041C>T (p.Arg681Ter) has not been reported in the 1000 genomes but has a MAF of 0.01% in the gnomAD database. The in silico prediction of the variant are damaging by DANN, LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo. In summary, the variant meets our criteria to be classified as a pathogenic variant.

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Around 20% of control neurofibromin levels are expressed (PMID: 27171602 (2016)).

This sequence change creates a premature translational stop signal (p.Arg681*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs768638173, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 10607834, 23404336, 25324867). ClinVar contains an entry for this variant (Variation ID: 188280). For these reasons, this variant has been classified as Pathogenic.

The NF1 c.2041C>T; p.Arg681Ter variant (rs768638173) is reported in the literature in individuals with neurofibromatosis type 1 (NF1) (Ars 2000, Kim 2014, Violante 2013). Functional analyses show the variant significantly decreases NF1 gene expression and function (Li 2016, Toonen 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 188280), and is found in the general population with a very low allele frequency of 0.0004% (1/245466 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Ars E et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet. 2000 Jan 22;9(2):237-47. Kim MJ et al. Neurofibromatosis type 1: a single center's experience in Korea. Korean J Pediatr.2014 Sep;57(9):410-5. Li K et al. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I. Dis Model Mech. 2016 Jul 1;9(7):759-67. Toonen JA et al. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1. Hum Mol Genet. 2016 May 1;25(9):1703-13. Violante IR et al. GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact. Brain. 2013 Mar;136(Pt 3):918-25.

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000398, PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000188280.12). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: reduced or absent protein expression and increased ERK phosphorylation/activation (Li 2016, Toonen 2016); This variant is associated with the following publications: (PMID: 25525159, 28881745, 26457647, 23404336, 26908603, 27171602, 25324867, 25325900, 28955729, 29522274, 31730495, 31533651, 31717729, 28124441, 10607834, 17668375, 19142971, 26973730, 16944272, 26666878, 22190595, 16941471, 21354044, 21031597, 18546366, 29415745, 31370276, 31776437, 33372952, 27482814, 33674644, 35547262)

PVS1+PM2_Supporting+PS4+PP4+PM6

In this first report of NF1 from Jammu and Kashmir India, Study of the NF1 family, indicating the autosomal dominant mode of transmission of NM_000267.3:c.2041C>T NF1 variation. In the family, the proband and two of his affected children were found to be heterozygous for the variation, whereas an unaffected child was found without the variation. Further, Affected grand-daughter was found heterozygous where as unaffected grandson was found not carrying the variation. The variation was seen perfectly segregating with the disease in the 3 generational family. Source OMIM: Neurofibromatosis type I (NF1) is caused by heterozygous mutation in the neurofibromin gene (NF1; 613113).

We report an NF1 variant that we associated with GIST tumour