Submissions for variant NM_001042492.3(NF1):c.6147+1G>A

dbSNP: rs1060500296

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461628	SCV000542068	pathogenic	Neurofibromatosis, type 1	2022-12-02	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 15146469). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 404489). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 40 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant disrupts the c.6084 nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22222937). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492241	SCV000581283	pathogenic	Hereditary cancer-predisposing syndrome	2015-07-22	criteria provided, single submitter	clinical testing	The c.6147+1G>A intronic pathogenic mutation (also known asc.6084+1G>A)results from a G to A substitutionone nucleotide after coding exon 41 of the NF1 gene.This variant was found in one individual who wasclinicallysuspected to have NF1; however,specific clinical details for thisindividual were not provided (De Luca A, et al. Hum. Mutat. 2004;23(6):629).A different alterationlocatedat the same nucleotideposition,c.6147+1G>T, was found in an individual who met NIH clinical criteria for NF1 (Bianco G, et al.Neurol. Sci. 2012;33(6):1483-5).In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000461628	SCV000782070	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000461628	SCV002560171	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000681857	SCV000809335	pathogenic	not provided	2018-09-16	no assertion criteria provided	research