Submissions for variant NM_001042492.3(NF1):c.60G>C (p.Gln20His)

dbSNP: rs1911559787

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001240243	SCV001413172	likely pathogenic	Neurofibromatosis, type 1	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 20 of the NF1 protein (p.Gln20His). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 31370276; Invitae). ClinVar contains an entry for this variant (Variation ID: 965727). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gln20 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31370276). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001559916	SCV001782237	likely pathogenic	not provided	2019-05-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31370276)
Genome-Nilou Lab	RCV001240243	SCV002561541	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001559916	SCV003917907	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	NF1: PM2, PS4:Moderate, PP4, PS3:Supporting