Submissions for variant NM_001042492.3(NF1):c.3906T>G (p.Asp1302Glu)

gnomAD frequency: 0.00001  dbSNP: rs549058591

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164143	SCV000214759	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-30	criteria provided, single submitter	clinical testing	The p.D1302E variant (also known as c.3906T>G), located in coding exon 29 of the NF1 gene, results from a T to G substitution at nucleotide position 3906. The aspartic acid at codon 1302 is replaced by glutamic 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 0.004% (greater than 110000 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is well conserved through sloth, however glutamic acid is the reference amino acid in lower 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.D1302E remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542427	SCV000628556	benign	Neurofibromatosis, type 1	2024-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000681119	SCV000808577	uncertain significance	not provided	2018-02-19	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.3906T>G at the cDNA level, p.Asp1302Glu (D1302E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a melanoma (Krauthammer 2015). NF1 Asp1302Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Thomas 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Asp1302Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV001125038	SCV001284068	uncertain significance	Neurofibromatosis, familial spinal	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001125039	SCV001284069	uncertain significance	Neurofibromatosis-Noonan syndrome	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000542427	SCV001284070	uncertain significance	Neurofibromatosis, type 1	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001125040	SCV001284071	uncertain significance	Café-au-lait macules with pulmonary stenosis	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000542427	SCV002560341	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558356	SCV005047755	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-11-01	criteria provided, single submitter	clinical testing	The c.3906T>G (p.D1302E) alteration is located in exon 29 (coding exon 29) of the NF1 gene. This alteration results from a T to G substitution at nucleotide position 3906, causing the aspartic acid (D) at amino acid position 1302 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005016487	SCV005646738	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-04-16	criteria provided, single submitter	clinical testing