Submissions for variant NM_001042492.3(NF1):c.4330A>C (p.Lys1444Gln)

dbSNP: rs137854550

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics, University of Parma	RCV000497192	SCV000588777	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000497192	SCV000782014	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Medical Genomics Laboratory, Department of Genetics UAB	RCV000497192	SCV000999185	pathogenic	Neurofibromatosis, type 1	2019-06-05	criteria provided, single submitter	clinical testing
Invitae	RCV000497192	SCV001584186	pathogenic	Neurofibromatosis, type 1	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1423 of the NF1 protein (p.Lys1423Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NF1-related conditions (PMID: 31595648). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431637). 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 disruptive. Experimental studies have shown that this missense change affects NF1 function (PMID: 8264648). This variant disrupts the p.Lys1423 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1568247, 11857752, 16380919, 16786508, 22807134, 23244495, 27322474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000497192	SCV002560035	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002329179	SCV002631548	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-21	criteria provided, single submitter	clinical testing	The p.K1423Q pathogenic mutation (also known as c.4267A>C), located in coding exon 31 of the NF1 gene, results from an A to C substitution at nucleotide position 4267. The lysine at codon 1423 is replaced by glutamine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV003105926	SCV003762082	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased GAP activity and affinity for Ras and reduced ability of neurofibromin to associate with microtubules (Xu and Gutmann, 1997; Poullet et al., 1994); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31066482, 23656349, 27716896, 29290338, 9219873, 25486365, 22807134, 8264648, 34080803, 31595648)