ClinVar Genomic variation as it relates to human health

The NF1 c.4600C>T; p.Arg1534Ter variant (rs760703505), also known as c.4537C>T; p.Arg1513Ter, is reported in the medical literature in several individuals affected with neurofibromatosis type 1 (Fahsold 2000, Hutter 2016, Jeong 2006, Ko 2013, Side 1997, Valero 2011). This reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 220152), and only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. 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: Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Hutter S et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet. 2016 May;135(5):469-75. Jeong SY et al. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci. 2006 Feb;21(1):107-12. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. Side L et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med. 1997 Jun 12;336(24):1713-20. Valero MC et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22.

PVS1, PS4, PM6, PP5

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated juvenile myelomonocytic leukemia (MIM#607785), familial spinal neurofibromatosis (MIM#162210), neurofibromatosis type 1 (MIM#162200), neurofibromatosis-Noonan syndrome (MIM#601321) and Watson syndrome (MIM#193520). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least ten NMD-predicted variants have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories and has been reported in individuals with neurofibromatosis type 1 (ClinVar; PMIDs: 23668869, 27838393). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Criteria applied: PVS1,PS4_MOD,PM2_SUP

This sequence change creates a premature translational stop signal (p.Arg1513*) 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 (rs760703505, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9180088, 10712197, 16479075, 21354044, 23668869, 26969325). ClinVar contains an entry for this variant (Variation ID: 220152). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

NF1: PVS1, PM2, PM6, PS4:Moderate, PP1

Variant summary: NF1 c.4537C>T (p.Arg1513X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251346 control chromosomes (gnomAD). The variant, c.4537C>T, had been reported as a recurring pathogenic variant in several individuals affected with Neurofibromatosis Type 1 (e.g. Side_1997, Frayling_2019, Yao_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.R1534* pathogenic mutation (also known as c.4600C>T), located in coding exon 35 of the NF1 gene, results from a C to T substitution at nucleotide position 4600. This changes the amino acid from an arginine to a stop codon within coding exon 35. This mutation has been observed in multiple neurofibromatosis type 1 (NF1) families,<span style="background-color:initial">including one family in which the mutation segregated with NF1 in a proband diagnosed with juvenile myelomonocytic leukemia at 14 months and his affected mother (<span style="background-color:initial">Ko JMet al. Pediatr. Neurol. 2013 Jun;48(6):447-53,Side Let al. N. Engl. J. Med. 1997 Jun;336(24):1713-20; ​DuatRodriguez A et al.AnPediatr(Barc). 2015 Sep;83(3):173-82<span style="background-color:initial">). In addition to the clinical information presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).<span style="background-color:initial">This mutation is also known as p.R1513* (c.4537C>T) in published literature.

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; This variant is associated with the following publications: (PMID: 10862084, 29957862, 16941471, 21354044, 18041031, 12552569, 17209131, 24676424, 22155606, 24789688, 27838393, 31717729, 31533797, 34427956, 31980526, 17914445, 10607834, 9180088, 25525159, 14517963, 23668869, 24932921, 29506128, 30530636, 10712197, 16479075, 26969325, 15060124, 15146469, 20687928, 31730495, 31533651, 31370276, 29625052, 32005694, 34426522, 34055682, 31776437, 33344560, 31783133)

PVS1, PP5, PP1, BS2

The NF1 c.4600C>T (p.Arg1534Ter) variant, also published as NF1 c.4537C>T, was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with neurofibromatosis type 1 (Chai et al., PMID 31533651; Ko et al., PMID: 23668869; Yao et al., PMID 31717729; Giuliano et al, PMID 31370276). NF1 c.4600C>T (p.Arg1534Ter) has been reported in the ClinVar database as pathogenic/likely pathogenic by 22 submitters (ClinVar ID 220152). This variant is only observed on 1/152116 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant leads to a premature termination codon, which is predicted to result in nonsense mediated decay and loss of function is the known disease mechanism. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and and gene-specific practices from the ClinGen Criteria Specification Registry, the NF1 c.4600C>T (p.Arg1534Ter) variant is classified as pathogenic.

The stop gained c.4600C>T (p.Arg1534Ter) variant in the NF1 gene has been been reported as a recurring pathogenic variant in several individuals affected with Neurofibromatosis Type 1 (Yao et al., 2019; Ko JM et al., 2013). This variant is reported with the allele frequency 0.0007% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). The nucleotide change c.4600C>T in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

We report the c.4537C>T (p.Arg1513*) in our family study because this variant it's associated with pheochromocytoma and GIST tumor