Submissions for variant NM_001042492.3(NF1):c.5160G>T (p.Glu1720Asp)

gnomAD frequency: 0.00001  dbSNP: rs773378630

Total submissions: 11

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	The p.E1720D variant (also known as c.5160G>T), located in coding exon 37 of the NF1 gene, results from a G to T substitution at nucleotide position 5160. The glutamic acid at codon 1720 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.E1720D remains unclear
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460990	SCV000542182	likely benign	Neurofibromatosis, type 1	2024-01-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000680828	SCV000808276	uncertain significance	not provided	2021-08-16	criteria provided, single submitter	clinical testing	Previously reported in at least one 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); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9691142, 31305009, 26489445, 32566746, 30287823, 25486365, 2121369, 22807134, 26510091)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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.
Ambry Genetics	RCV002338690	SCV002640547	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-08-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.