ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5097G>T (p.Glu1699Asp) (rs773378630)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219317 SCV000274770 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000460990 SCV000542182 uncertain significance Neurofibromatosis, type 1 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1699 of the NF1 protein (p.Glu1699Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs773378630, ExAC 0.01%). This variant has been reported in an individual with juvenile chronic myelogenous leukemia without neurofibromatosis type 1 (PMID: 9691142). ClinVar contains an entry for this variant (Variation ID: 231040). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000680828 SCV000808276 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing This variant is denoted NF1 c.5097G>T at the cDNA level, p.Glu1699Asp (E1699D) at the protein level,and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAT). This variant has been reported in at leastone individual with juvenile chronic myelogenous leukemia, without a personal history of Neurofibromatosis Type 1(NF1), and was also absent in 65 healthy controls (Watanabe 1998). NF1 Glu1699Asp was not observed at asignificant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 GenomesConsortium 2015, Lek 2016). Since Glutamic Acid and Aspartic Acid share similar properties, this is considered aconservative amino acid substitution. NF1 Glu1699Asp occurs at a position where amino acids with properties similarto Glutamic Acid are tolerated across species and is not located in a known functional domain. In silico analyses areinconsistent regarding the effect this variant may have on protein structure and function. Based on currently availableevidence, it is unclear whether NF1 Glu1699Asp is a pathogenic or benign variant. We consider it to be a variant ofuncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780547 SCV000917893 benign not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: NF1 c.5097G>T (p.Glu1699Asp) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 297828 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0043 within the Japanese subpopulation (Momozawa_2018). The observed variant frequency within Japanese control individuals reported by Momozawa_2018 is approximately 5,700 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Juvenile Myelomonocytic Leukemia phenotype (7.5e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Japanese origin. c.5097G>T has been reported in the literature in individuals affected with Juvenile Myelomonocytic Leukemia and breast cancer, all of them were of Japanese origin (Watanabe_1998, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Juvenile Myelomonocytic Leukemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000460990 SCV001140378 uncertain significance Neurofibromatosis, type 1 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030578 SCV001193668 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV001126130 SCV001285289 uncertain significance Neurofibromatosis-Noonan syndrome 2017-07-11 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000460990 SCV001285290 uncertain significance Neurofibromatosis, type 1 2017-06-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001126131 SCV001285291 uncertain significance Café-au-lait macules with pulmonary stenosis 2017-06-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001126132 SCV001285292 uncertain significance Neurofibromatosis, familial spinal 2017-06-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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