ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.4330A>G (p.Lys1444Glu) (rs137854550)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000000364 SCV000271424 pathogenic Neurofibromatosis, type 1 2015-06-09 criteria provided, single submitter clinical testing The p.Lys1444Glu variant in NF1 (p.Lys1423Glu on transcript NM_000267.3) has bee n previously reported in at least 5 individuals with Neurofibromatosis type 1 an d segregated with disease in 4 affected family members from 1 family (Li 1992, U padhyaya 1997, Upadhyaya 2004, Laycock-VanSpyke 2011 ). In addition, it has been identified as a somatic variant in individuals with colon adenocarcinoma, anapl astic astrocytoma, and myelodysplasitc syndrome (Li 1992). This variant has also been identified in 1/65426 European chromosomes by the Exome Aggregation Consor tium (ExAC,; dbSNP rs137854550). Please note that for diseases with variable expressivity, pathogenic variants may be present at a low frequency in the general population. Furthermore, in-vitro functional stud ies provide some evidence that this variant may impact protein function (Li 1992 , Poullet 1994, Thomas 2012). This variant is located in the last three bases of the exon, which is part of the 5? splice region, and computational tools sugges t a possible impact to splicing. However, in vitro assays and computational too ls may not accurately represent biological function. In summary, this variant m eets our criteria to be classified as pathogenic for neurofibromatosis type 1 in an autosomal dominant manner ( based upon segregation studies and functional evidence.
GeneDx RCV000489593 SCV000576670 pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted NF1 c.4267A>G at the cDNA level, p.Lys1423Glu (K1423E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has been observed in multiple individuals with Neurofibromatosis type 1 syndrome (NF1) and demonstrated complete segregation with disease in one family (Li 1992, Upadhyaya 1997, Upadhyaya 2004, Laycock-van Spyk 2011, Alkindy 2012, Evans 2016). Additionally, NF1 Lys1423Glu was reported in two pediatric patients with a NF1/Noonan syndrome phenotype (De Luca 2005). In vitro functional studies also revealed this variant to have reduced GTPase-activating protein (GAP) activity compared to wild type (Li 1992, Poullet 1994, Thomas 2012).NF1 Lys1423Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Lys1423Glu occurs at a position that is conserved across species and is located in the Ras-GAP domain (UniProt). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000492352 SCV000581338 pathogenic Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing The p.K1423E variant (also known as c.4267A>G), located in coding exon 31 of the NF1 gene, results from an A to G substitution at nucleotide position 4267. The lysine at codon 1423 is replaced by glutamic acid, an amino acid with similar properties. This mutation was detected in an NF1 family with perfect segregation among six (four affected who met NIH diagnostic criteria and two unaffected) family members (Li Y, et al. Cell 1992; 69(2):275-81). This mutation has also been detected in several individuals who met NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cassiman C et al. Clin. Genet., 2017 Apr;91:529-535; Cannon A et al. Orphanet J Rare Dis, 2018 Feb;13:31; Upadhyaya M, et al. Hum. Mutat. 2008; 29(8):E103-11; Thomas L, et al. Hum. Mutat. 2012;33(12):1687-96; Pros E, et al. Hum. Mutat. 2008;29(9):E173-93; Wang Q, et al. Hum. Genet. 2003;112(2):117-23) and in several individuals with Noonan syndrome features (De Luca A, et al. Am. J. Hum. Genet. 2005; 77(6):1092-101). In addition, this mutation is located in the conserved catalytic domain of the NF1 gene suggesting that it has a crucial function in NF1 GRD activity. Functional studies have shown this mutation to be incapable of suppressing heat shock sensitivity in vitro, (wild-type efficiently suppressed heat shock sensitivity) and to have reduced GAP activity and microtubule association compared with the wild-type protein. This mutation was also shown to have a 200 fold reduction in GTPase stimulating activity but had the same affinity of rasGTP to inhibit NF1 GRD stimulated hydrolysis of rasGTP as wild-type (Poullet P, et al. Mol. Cell. Biol. 1994;14(1):815-21; Xu H, et al. Brain Res. 1997; 759(1):149-52; Li Y, et al. Cell 1992; 69(2):275-81). Based on the supporting evidence, p.K1423E is interpreted as a disease-causing mutation.
Invitae RCV000000364 SCV000628580 pathogenic Neurofibromatosis, type 1 2020-09-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1423 of the NF1 protein (p.Lys1423Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs137854550, ExAC 0.002%). This variant has been reported in several families and individuals affected with neurofibromatosis type 1 (PMID: 1568247, 11857752, 23244495, 16786508). In at least one affected individual, this variant arose de novo (PMID: 27322474). It has also been reported in two individuals affected with neurofibromatosis-Noonan syndrome (PMID: 16380919). ClinVar contains an entry for this variant (Variation ID: 336). Experimental studies have shown that this missense change reduces protein activity 200-400-fold compared with wild type (PMID: 1568247, 22807134), and that the lysine residue is specifically required for normal protein function (PMID: 8264648). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626644 SCV000747346 pathogenic Neurofibromatosis type 6; Neurofibroma; Axillary freckling; Optic nerve glioma 2017-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762990 SCV000893435 pathogenic Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
Medical Genomics Laboratory,Department of Genetics UAB RCV000000364 SCV000999186 pathogenic Neurofibromatosis, type 1 2019-06-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000000364 SCV001366253 pathogenic Neurofibromatosis, type 1 2018-10-19 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3.
Athena Diagnostics Inc RCV000489593 SCV001476709 pathogenic not provided 2020-09-11 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including at least one apparent de novo. Not found in the total gnomAD dataset, but the area has low coverage, or is a low quality site. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family.
Baylor Genetics RCV000000364 SCV001523054 pathogenic Neurofibromatosis, type 1 2020-06-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000000364 SCV000020508 pathogenic Neurofibromatosis, type 1 1992-04-17 no assertion criteria provided literature only
Medical Genetics, University of Parma RCV000000364 SCV000588778 uncertain significance Neurofibromatosis, type 1 2017-02-02 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000489593 SCV001808027 pathogenic not provided no assertion criteria provided clinical testing

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