Submissions for variant NM_001042492.3(NF1):c.1330G>C (p.Gly444Arg)

dbSNP: rs1162173842

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566895	SCV000663070	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-30	criteria provided, single submitter	clinical testing	The p.G444R variant (also known as c.1330G>C), located in coding exon 12 of the NF1 gene, results from a G to C substitution at nucleotide position 1330. The glycine at codon 444 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000alleles tested) in our clinical cohort.This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.G444Rremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812785	SCV000953110	uncertain significance	Neurofibromatosis, type 1	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 444 of the NF1 protein (p.Gly444Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 480083). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000812785	SCV002561893	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559223	SCV005047512	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-11-29	criteria provided, single submitter	clinical testing	The c.1330G>C (p.G444R) alteration is located in exon 12 (coding exon 12) of the NF1 gene. This alteration results from a G to C substitution at nucleotide position 1330, causing the glycine (G) at amino acid position 444 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.