Submissions for variant NM_001042492.3(NF1):c.847G>T (p.Asp283Tyr)

gnomAD frequency: 0.00002  dbSNP: rs200572531

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205213	SCV000261381	uncertain significance	Neurofibromatosis, type 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 283 of the NF1 protein (p.Asp283Tyr). This variant is present in population databases (rs200572531, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 41680). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027794	SCV001190404	uncertain significance	Neurofibromatosis, familial spinal; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2019-07-15	criteria provided, single submitter	clinical testing	NF1 NM_000267.3 exon 8 p.Asp283Tyr (c.847G>T): This variant has not been reported in the literature and is present in 0.006% (1/16242) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-29509642-G-T). This variant is present in ClinVar (Variation ID:41680). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome-Nilou Lab	RCV000205213	SCV002561834	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000034592	SCV002577273	uncertain significance	not provided	2022-09-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22703879)
Ambry Genetics	RCV003764658	SCV002681595	likely benign	Cardiovascular phenotype	2020-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: observed 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.
Fulgent Genetics, Fulgent Genetics	RCV002490460	SCV002784445	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-12-07	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002490460	SCV003920274	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-03-30	criteria provided, single submitter	clinical testing	NF1 NM_000267.3 exon 8 p.Asp283Tyr (c.847G>T): This variant has not been reported in the literature and is present in 0.006% (1/16242) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-29509642-G-T). This variant is present in ClinVar (Variation ID:41680). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034592	SCV000043385	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.