Submissions for variant NM_001042492.3(NF1):c.1005T>C (p.Asn335=)

gnomAD frequency: 0.00011  dbSNP: rs777369021

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163833	SCV000214419	likely benign	Hereditary cancer-predisposing syndrome	2020-09-02	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199777	SCV000253197	benign	Neurofibromatosis, type 1	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000613914	SCV000718635	likely benign	not specified	2018-01-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000613914	SCV001362235	likely benign	not specified	2019-03-14	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1005T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-05 in 277190 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (8.3e-05 vs 0.00021), allowing no conclusion about variant significance. This variant has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Gasparini_1996, Bottillo_2007), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. Co-occurrences with other pathogenic variant have been reported (Bottillo_2007; NF1 c.476delC , p.Arg160Glyfs*5), providing supporting evidence for a benign role. In an in vitro mini gene assay, the variant was shown to abolish an expression of an alternative transcript lacking exon 7, however the clinical significance of this outcome is unclear (Bottillo_2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000613914	SCV002068089	likely benign	not specified	2020-04-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163833	SCV002527369	likely benign	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000199777	SCV002561839	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498812	SCV002811373	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-10-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316009	SCV004016412	benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing