Submissions for variant NM_001042492.3(NF1):c.6685T>C (p.Trp2229Arg)

dbSNP: rs1060500342

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476768	SCV000542150	pathogenic	Neurofibromatosis, type 1	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2208 of the NF1 protein (p.Trp2208Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (NF1) (Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 404554). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492440	SCV000581264	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-23	criteria provided, single submitter	clinical testing	The p.W2229R variant (also known as c.6685T>C), located in coding exon 43 of the NF1 gene, results from a T to C substitution at nucleotide position 6622. The tryptophan at codon 2208 is replaced by arginine, an amino acid with dissimilar properties. The variant was detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 and co-segregated with disease in one family (Ambry internal data). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome-Nilou Lab	RCV000476768	SCV002560202	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365593	SCV002663170	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-08-21	criteria provided, single submitter	clinical testing	The p.W2208R variant (also known as c.6622T>C), located in coding exon 43 of the NF1 gene, results from a T to C substitution at nucleotide position 6622. The tryptophan at codon 2208 is replaced by arginine, an amino acid with dissimilar properties. The variant was detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 and co-segregated with disease in one family, and has been observed in additional individuals with a personal and/or family history that is consistent with NF1-related disease (Ambry internal data). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.