17-31235728-C-G

Variant names:

• chr17-31235728-C-G
• rs199474742
• NM_001042492.3:c.3826C>G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.3826C>G​(p.Arg1276Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,130 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. R1276L) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 3.24

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Ras-GAP (size 216) in uniprot entity NF1_HUMAN there are 42 pathogenic changes around while only 3 benign (93%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31235729-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-31235728-C-G is Pathogenic according to our data. Variant chr17-31235728-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31235728-C-G is described in Lovd as [Pathogenic]. Variant chr17-31235728-C-G is described in Lovd as [Pathogenic]. Variant chr17-31235728-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3826C>G	p.Arg1276Gly	missense_variant	Exon 28 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3826C>G	p.Arg1276Gly	missense_variant	Exon 28 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3826C>G	p.Arg1276Gly	missense_variant	Exon 28 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:5

Jun 05, 2019

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_000267.3(NF1):c.3826C>G, has been identified in exon 28 of 57 of the NF1 gene. The variant is predicted to result in a major amino acid change from arginine to glycine at position 1276 of the protein (NP_000258.1(NF1):p.(Arg1276Gly)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the RasGAP neurofibromin domain. The Arg1276 residue is the arginine finger in the GAP-related domain, essential for the catalytic activity of the protein (De Luca A. et al. 2005). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database, and has previously been reported in patients with neurofibromatosis type 1 (Mattocks C. et al. 2004, ClinVar). Two different variants in the same codon resulting in a change to glutamine and proline has also been reported in patients with the same condition (Klose A. et al. (1998), Fahsold R. et al. (2000)). Analysis of parental samples indicated this variant is de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Dec 04, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.3826C>G (p.Arg1276Gly) results in a non-conservative amino acid change located in the Ras GTPase-activating domain (IPR001936) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251202 control chromosomes (gnomAD). c.3826C>G has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (e.g. Mattocks_2004, Koczkowska_2020, Lunke_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant exhibits dramatically increased affinity for wild-type H-ras protein compared with the wild-type NF1-GRD (Morcos_1996) however, the clinical significance of this finding is unknown. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1276 of the NF1 protein (p.Arg1276Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis 1 (NF1) (PMID: 15060124, 31595648). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68340). 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%. Experimental studies have shown that this missense change affects NF1 function (PMID: 8628317). This variant disrupts the p.Arg1276 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9302992, 10712197, 15060124, 16479075, 19221814, 22807134, 23668869, 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. -

not provided Pathogenic:2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Aug 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated patients from different ethnic backgrounds with neurofibromatosis 1 in published literature (Mattocks et al., 2004; Koczkowska et al., 2020) and not observed in controls; Individuals with Arg1276 residue variants are reported as more likely to display Noonan-like features (Koczkowska et al., 2020); 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; Published functional studies demonstrate an increased binding affinity for H-ras, the significance of which is uncertain (Morcos et al., 1996); This variant is associated with the following publications: (PMID: 15863657, 15060124, 24803665, 9687500, 25486365, 22807134, 8628317, 32573669, 31595648) -

not specified Pathogenic:1

Jan 20, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NF1-related disorder Pathogenic:1

Jun 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3826C>G variant is predicted to result in the amino acid substitution p.Arg1276Gly. This variant has been reported in multiple individuals with neurofibromatosis type 1 (Mattocks et al. 2004. PubMed ID: 15060124; Koczkowska et al. 2019. PubMed ID: 31595648). Functional studies found this variant leads to increased affinity for HRAS (Morcos et al. 1996. PubMed ID: 8628317) and a reduction in Ras GAP activity (Douben et al. 2023. Human Mutation. vol. 2023. Article ID 9628049). Studies show that Arg1276 is a critical residue for catalyzing the hydrolysis of active Ras-GTP to inactive Ras-GDP (Ahmadian et al. 1997. PubMed ID: 9302992). Furthermore, alternate missense variants at this position (p.Arg1276Gln, p.Arg1276Pro, p.Arg1276Leu) are also reported as pathogenic (Koczkowska et al. 2019. PubMed ID: 31595648). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and is interpreted as likely pathogenic/pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/68340/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Nov 16, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1276G pathogenic mutation (also known as c.3826C>G), located in coding exon 28 of the NF1 gene, results from a C to G substitution at nucleotide position 3826. The arginine at codon 1276 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals fulfilling diagnostic criteria for neurofibromatosis type 1 (NF1) (Koczkowska M et al. Hum Mutat, 2020 01;41:299-315; Castellanos E et al. Clin Genet, 2020 02;97:264-275). Another alteration at the same codon, p.R1276Q (c.3827G>A), has been detected in multiple indiviudals fulfilling diagnostic criteria for NF1 (Mattocks C et al. J. Med. Genet. 2004 Apr;41:e48; Wimmer K et al. Hum. Mutat. 2007 Jun;28:599-612; Ko JM et al. Pediatr. Neurol. 2013 Jun;48:447-53; Evans DG et al. EBioMedicine 2016 May;7:212-20) and has been shown to impair protein function (Wallis D et al. Hum. Mutat., 2018 06;39:816-821). This alteration disrupts a crucial motif that enables NF1 to activate GTP hydrolysis in Ras proteins (Ambry internal data). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.94		Loss of methylation at R1276 (P = 0.0339);Loss of methylation at R1276 (P = 0.0339);.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199474742; hg19: chr17-29562746; COSMIC: COSV104662235;