17-31229155-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001042492.3(NF1):c.2540T>C(p.Leu847Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. L847R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 7.64

Variant links:

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]

NF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31229155-T-G 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, 0.968

PP5

Variant 17-31229155-T-C is Pathogenic according to our data. Variant chr17-31229155-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229155-T-C is described in Lovd as [Pathogenic]. Variant chr17-31229155-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.2540T>C	p.Leu847Pro	missense_variant	Exon 21 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.2540T>C	p.Leu847Pro	missense_variant	Exon 21 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.2540T>C	p.Leu847Pro	missense_variant	Exon 21 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459586

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:12

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2540T>C;p.(Leu847Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 68323; PMID: 10712197; 12552569; 15146469; 23668869; 24413922; 10862084) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (hot-spot region) - PM1. This variant is not present in population databases (rs199474747, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 573019) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 24413922, 12552569) - PM6. Missense variant in NF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2019

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 847 of the NF1 protein (p.Leu847Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 10862084, 12552569, 15146469, 23668869, 24413922). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68323). 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 expected to disrupt NF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect NF1 function (PMID: 16513807). For these reasons, this variant has been classified as Pathogenic. -

Oct 22, 2019

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.2540T>C (p.Leu847Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250444 control chromosomes (gnomAD). c.2540T>C has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (Fahsold_2000, Koczkowska_2018). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submissions (evaluation after 2014) cite the variant four times as likely pathogenic and three times as pathogenic. In addition, another variant affecting the same codon, p.Leu847Arg, has been reported to associate with Neurofibromatosis 1 (via HGMD database). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 31, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely 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

- -

Jul 01, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 34418705, 32980694, 24803665, 26432421, 12552569, 27838393, 16513807, 15146469, 27322474, 10712197, 16944272, 23668869, 10862084, 23758643, 29483232, 30530636, 32814709, 25486365, 2121369, 29926297, 29968256, 30014477, 29290338, 30308447, 31776437, 30287823, 31766501, 34694046, 35119474, 29559732, 24413922) -

not specified

Pathogenic:1

Sep 29, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Pathogenic:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1 NM_000267.3 exon 21 p.Leu847Pro (c.2540T>C): This variant has been reported in the literature in numerous individuals with Neurofibromatosis type 1, segregating with disease in several affected family members (Fahsold 2000 PMID:10712197, McPherson 2015 PMID:26432421, Koczkowska 2018 PMID:29290338, Frayling 2019 PMID:30530636). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:68323). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. Other variants at this position and nearby amino acids have been reported in association with disease; at least 1 publication cites exon 21 (in which this variant is located) as a mutational hotspot (Koczkowska 2018 PMID:29290338). In summary, this variant is classified as pathogenic based on the data above. -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Juvenile myelomonocytic leukemia

Pathogenic:1

May 21, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Café-au-lait macules with pulmonary stenosis

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4,PS2,PM2,PP3,PM5,PP1 -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Jan 23, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L847P pathogenic mutation (also known as c.2540T>C), located in coding exon 21 of the NF1 gene, results from a T to C substitution at nucleotide position 2540. The leucine at codon 847 is replaced by proline, an amino acid with similar properties. This variant occurs in a hotspot for missense mutations within NF1 and has been detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (NF1) (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Griffiths S et al. Fam Cancer, 2007;6:21-34; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Nemethova M et al. Ann Hum Genet, 2013 Sep;77:364-79; Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87; Tsipi M et al. J. Neurol. Sci., 2018 12;395:95-105). In a large cohort study, the variant was detected de novo in five individuals with NF1 and co-segregated with disease in five families (Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 16, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L847P variant (also known as c.2540T>C), located in coding exon 21 of the NF1 gene, results from a T to C substitution at nucleotide position 2540. The leucine at codon 847 is replaced by proline, an amino acid with similar properties. This variant has been described in multiple cohorts of NF1 patients (Fahsold R et al.Am. J. Hum. Genet. 2000 Mar; 66(3):790-818, Griffiths S et al. Fam. Cancer 2007; 6(1):21-34, Ko JM et al. Pediatr. Neurol. 2013 Jun; 48(6):447-53, Nemethova M et al. Ann. Hum. Genet. 2013 Sep; 77(5):364-79).This variant was previously reported in the SNPDatabase as rs199474747 butwas not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 55,000 alleles tested) in our clinical cohort.This amino acid position is highly conserved on sequence alignment of 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. -

Atypical coarctation of aorta

Pathogenic:1

Feb 26, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.99

MutPred

0.88

Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);.;

MVP

0.89

MPC

2.2

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over