Submissions for variant NM_001042492.3(NF1):c.6428-2A>G

dbSNP: rs1060500312

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462301	SCV000542091	pathogenic	Neurofibromatosis, type 1	2023-06-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 404510). Disruption of this splice site has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 16740526, 26178382). 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 affects an acceptor splice site in intron 41 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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810945	SCV002050151	pathogenic	not provided	2020-10-19	criteria provided, single submitter	clinical testing	The NF1 c.6428-2A>G variant (rs1060500312) is reported in the literature in several individuals affected with neurofibromatosis type 1, including at least one individual in which the variant occurred de novo (Altarescu 2006, Rojnueangnit 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 42, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Altarescu G et al. Single-sperm analysis for haplotype construction of de-novo paternal mutations: application to PGD for neurofibromatosis type 1. Hum Reprod. 2006 Aug;21(8):2047-51. Rojnueangnit K et al. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation. Hum Mutat. 2015 Nov;36(11):1052-63.
Genome-Nilou Lab	RCV000462301	SCV002560183	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003168737	SCV003893839	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-02-06	criteria provided, single submitter	clinical testing	The c.6365-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 42 in the NF1 gene. This alteration has been reported in one individual with features of NF1-related disease (Rojnueangnit K et al. Hum Mutat 2015 Nov;36(11):1052-63). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.