Submissions for variant NM_001042492.3(NF1):c.3665del (p.Pro1222fs)

dbSNP: rs867391752

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757564	SCV000885850	pathogenic	not specified	2018-12-12	criteria provided, single submitter	clinical testing	The NF1 c.3665delC; p.Pro1222fs variant (rs867391752) has been described in at least one individual affected with neurofibromatosis type 1 (Bonatti 2017). It is reported as pathogenic by one laboratory in ClinVar (Variation ID: 431627) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Bonatti F et al. Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I. Int J Mol Sci. 2017 Sep 29;18(10).
Invitae	RCV000497113	SCV001387279	pathogenic	Neurofibromatosis, type 1	2022-10-02	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 431627). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 28961165). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1222Leufs*2) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000497113	SCV002559978	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000497113	SCV002584745	pathogenic	Neurofibromatosis, type 1	2022-07-15	criteria provided, single submitter	clinical testing	The NF1 c.3665del (p.Pro1222LeufsTer2) change deletes 1 nucleotide in exon 27 of the NF1 gene to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 28961165, internal data). In one case, the variant was determined to be de novo in the affected individual (PMID: 28961165). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 9003501, 10712197). In summary, this variant meets criteria to be classified as pathogenic.
GeneDx	RCV003325486	SCV004031760	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34427956, 28961165)
Medical Genetics, University of Parma	RCV000497113	SCV000588767	pathogenic	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing