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

gnomAD frequency: 0.00002  dbSNP: rs137854550

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; 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 (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies and functional evidence.
GeneDx	RCV000489593	SCV000576670	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced GTPase-activating protein activity (Li 1992, Poullet 1994, Thomas 2012); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 16513807, 22807134, 8264648, 27322474, 1568247, 14722917, 18546366, 9003501, 22155606, 19845691, 23244495, 16380919, 9219873, 11857752, 29673180, 29415745, 31595648, 29625052, 16786508, 31730495, 31776437, 25486365, 33443663)
Ambry Genetics	RCV002310992	SCV000581338	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-12-17	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; Stella A et al. Genes (Basel), 2018 Apr;9:) and in several individuals with Noonan syndrome features (De Luca A, et al. Am. J. Hum. Genet. 2005; 77(6):1092-101). Functional analysis of this alteration in an in vitro Ras-activation assay shows significantly elevated levels of activated Ras compared to wild type (Thomas L et al. Hum. Mutat. 2012 Dec;33:1687-96). Based on the supporting evidence, p.K1423E is interpreted as a disease-causing mutation.
Invitae	RCV000000364	SCV000628580	pathogenic	Neurofibromatosis, type 1	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1423 of the NF1 protein (p.Lys1423Glu). 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 neurofibromatosis-Noonan syndrome (PMID: 1568247, 11857752, 16380919, 16786508, 23244495, 27322474). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 336). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NF1 function (PMID: 1568247, 8264648, 22807134). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626644	SCV000747346	pathogenic	Cafe au lait spots, multiple; 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	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including at least one apparent de novo. In some published literature, this variant is referred to as c.4330A>G, p.Lys1444Glu. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant significantly reduced the protein's ability to activate GTPase (PMID: 1568247, 8264648, 22807134). This is implicated in loss of p21 regulation, ras signaling interference and tumorigenesis. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
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].
Genome-Nilou Lab	RCV000000364	SCV002560036	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Department of Medicine, University of Texas Health Science Center at San Antonio	RCV002305424	SCV002571738	pathogenic	Pheochromocytoma	2022-09-14	criteria provided, single submitter	research	The following PIDs represent publications in which this variant has been detected and evaluated both in clinical contexts (patient-derived samples) and by in vitro experiments, and all of them support the pathogenic nature of this variant. These publications report on detection of this variant in germline disease (neurofibromatosis type 1) and as a somatic event in various cancer types. Moreover, there are multiple additional submissions to ClinVar that report this variant, mostly in the context of germline disease. We detected this variant as a somatic event accompanied by LOH of the wild-type allele in a patient that had a sporadic pheochromocytoma, but not neurofibromatosis type 1.
Baylor Genetics	RCV003460397	SCV004190767	pathogenic	Juvenile myelomonocytic leukemia	2023-02-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000489593	SCV004222170	pathogenic	not provided	2020-09-11	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals and families with NF1 in the published literature (PMID: 29415745 (2018), 23244495 (2012), 18546366 (2008), 16380919 (2005), 11857752 (2002), 9003501 (1997), 1568247 (1992)), including in a family where it segregated with disease (PMID: 1568247 (1992)). This variant has been reported as a de novo event (PMID: 27322474 (2016)). Functional data suggest that the variant is detrimental to normal protein function (PMID: 22807134 (2012), 16513807 (2006), 9219873 (1997), 9003501 (1997), 8264648 (1994)). Based on the available information, this variant is classified as pathogenic.
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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000489593	SCV001975412	pathogenic	not provided		no assertion criteria provided	clinical testing