Total submissions: 20
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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. |
Labcorp Genetics |
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, |
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, |
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 | |
UAB Medical Genomics Laboratory, |
RCV000000364 | SCV000999186 | pathogenic | Neurofibromatosis, type 1 | 2019-06-05 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
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 | 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- |
RCV000000364 | SCV002560036 | pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
Department of Medicine, |
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 | 2023-12-21 | 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. |
Clinical Genetics Laboratory, |
RCV000489593 | SCV005196970 | pathogenic | not provided | 2023-06-07 | criteria provided, single submitter | clinical testing | |
NHS Central & South Genomic Laboratory Hub | RCV000000364 | SCV005395914 | pathogenic | Neurofibromatosis, type 1 | 2024-11-12 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000000364 | SCV000020508 | pathogenic | Neurofibromatosis, type 1 | 1992-04-17 | no assertion criteria provided | literature only | |
Medical Genetics, |
RCV000000364 | SCV000588778 | uncertain significance | Neurofibromatosis, type 1 | 2017-02-02 | no assertion criteria provided | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000489593 | SCV001808027 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000489593 | SCV001975412 | pathogenic | not provided | no assertion criteria provided | clinical testing |