chr17-31233115-C-G
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.3610C>G(p.Arg1204Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1204Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3610C>G | p.Arg1204Gly | missense_variant | 27/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3610C>G | p.Arg1204Gly | missense_variant | 27/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3610C>G | p.Arg1204Gly | missense_variant | 27/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251386Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135844
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NF1 function (PMID: 22807134). 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. ClinVar contains an entry for this variant (Variation ID: 68337). 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. This variant is present in population databases (rs199474732, gnomAD 0.004%). 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Apr 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 07, 2023 | The de novo c.3610C>G p.(Arg1204Gly) missense variant identified in NF1 has been reported in the literature in multiple individuals with Neurofibromatosis Type 1 [PMID: 10336779, 22807134; 31370276]. The c.3610C>G variant has been deposited in ClinVar as Likely Pathogenic/Pathogenic bymultiple submitters [ClinVar ID: 68337], is absent from the gnomAD v3.1.2 and TOPMed Freeze 8 databases and has an allele frequency of 0.000003978 in the gnomAD v2.1.1 database, suggesting it is not a common benign variant in the populations represented in those databases. The c.3610C>G variant is located in exon27 of this 58-exon gene and is predicted to replace a highly conserved arginine with glycine at position 1204 of the encoded protein. In silico predictions neither support or refute a damaging effect [REVEL 0.571], but functional studies conducted in vitro have shown association with significantly elevated levels of activatedGTP-bound Ras by comparison with the wild-type NF1 protein [PMID: 22807134]. Three other variants at the same codon, p.(Arg1204Trp), p.(Arg1204Leu) andp.(Arg1204Gln), have also been reported [PMID: 22807134, 26635368]. Based on the available evidence, the de novo c.3610C>G p.(Arg1204Gly)missense variant identified in the NF1 gene is reported as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 26, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 07, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM5 moderated, PM6 moderated, PP2 supporting - |
not provided Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2023 | Published functional studies support a damaging effect: significant reduction in GTPase activity and mild reduction of interaction with SPRED1 (Thomas et al., 2012; Hirata et al., 2016); 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: 27322474, 22807134, 26633542, 26635368, 24803665, 10712197, 10336779, 23447461, 31370276, 31766501, 25486365) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 22, 2020 | 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. - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2019 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at