Submissions for variant NM_001042492.3(NF1):c.3610C>G (p.Arg1204Gly)

dbSNP: rs199474732

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000059189	SCV000490665	pathogenic	not provided	2021-08-10	criteria provided, single submitter	clinical testing	Published functional studies support a damaging effect: significant reduction in GTPase activity and mild reduction of interaction with SPRED1 (Thomas 2012, Hirata 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26635368, 22807134, 31766501, 25486365, 31370276, 27322474, 23447461, 10336779, 10712197, 24803665, 26633542)
Invitae	RCV000632346	SCV000753524	pathogenic	Neurofibromatosis, type 1	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1204 of the NF1 protein (p.Arg1204Gly). This variant is present in population databases (rs199474732, gnomAD 0.004%). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10336779, 26635368, 27322474; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68337). 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. Experimental studies have shown that this missense change affects NF1 function (PMID: 22807134). For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000632346	SCV000899247	pathogenic	Neurofibromatosis, type 1	2019-04-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002318949	SCV001182235	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-03-19	criteria provided, single submitter	clinical testing	The p.R1204G variant (also known as c.3610C>G), located in coding exon 27 of the NF1 gene, results from a C to G substitution at nucleotide position 3610. The arginine at codon 1204 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified an individual meeting NF1 diagnostic criteria (Krkljus S et al. Hum. Mutat., 1998;11:411). This variant has also been detected de novo in multiple unrelated individuals with NF1 (Hirata Y et al. J. Biol. Chem., 2016 Feb;291:3124-34). Experimental studies indicate that this variant will disrupt protein function (Thomas L et al. Hum. Mutat., 2012 Dec;33:1687-96). A different alteration at the same amino acid position, p.R1204W, has been identified in an individual meeting NF1 diagnostic criteria (Ars E et al. Hum. Mol. Genet., 2000 Jan;9:237-47). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000632346	SCV001479235	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000059189	SCV001879392	likely pathogenic	not provided	2020-09-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least two individuals with clinical features associated with this gene, with one of those appearing to occur de novo. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show a reduction in activity of the GAP-related domain of NF1 (PMID: 22807134, 26635368). Computational tools predict that this variant is damaging.
Genome-Nilou Lab	RCV000632346	SCV002559975	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000632346	SCV003807283	pathogenic	Neurofibromatosis, type 1	2022-10-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM5 moderated, PM6 moderated, PP2 supporting
UniProtKB/Swiss-Prot	RCV000059189	SCV000090718	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000059189	SCV001956904	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000059189	SCV001967662	pathogenic	not provided		no assertion criteria provided	clinical testing