Submissions for variant NM_001042492.3(NF1):c.4526G>A (p.Arg1509His)

gnomAD frequency: 0.00006  dbSNP: rs546073780

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129797	SCV000184606	likely benign	Hereditary cancer-predisposing syndrome	2016-02-05	criteria provided, single submitter	clinical testing	in silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or Conflicting Evidence
Invitae	RCV000205307	SCV000260956	likely benign	Neurofibromatosis, type 1	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000680997	SCV000808446	uncertain significance	not provided	2022-02-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with cafe-au-lait macules in published literature who had a different genetic etiology for the phenotype (Koczkowska 2018); This variant is associated with the following publications: (PMID: 22675565, 26919320, 29290338, 30613976, 22807134)
Athena Diagnostics	RCV000680997	SCV000842890	uncertain significance	not provided	2017-10-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818305	SCV002066761	uncertain significance	not specified	2021-01-07	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.015% in the non-Finnish subpopulation (dbSNP rs546073780). The p.Arg1488His change affects a highly conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1488His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1488His change remains unknown at this time.
Sema4, Sema4	RCV000129797	SCV002527573	likely benign	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	curation
Medical Genetics, University of Parma	RCV000205307	SCV002567757	likely benign	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326843	SCV002638463	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-01-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129797	SCV002819188	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483497	SCV004228524	not provided	Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-21-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.