17-31229146-T-C

Variant names:

• chr17-31229146-T-C
• rs137854566
• NM_001042492.3:c.2531T>C

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.2531T>C​(p.Leu844Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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. L844F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.64

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 helix (size 14) in uniprot entity NF1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 chr17-31229145-C-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, 0.981
• PP5: Variant 17-31229146-T-C is Pathogenic according to our data. Variant chr17-31229146-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229146-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2531T>C	p.Leu844Pro	missense_variant	Exon 21 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2531T>C	p.Leu844Pro	missense_variant	Exon 21 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2531T>C	p.Leu844Pro	missense_variant	Exon 21 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:5

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2023

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 844 of the NF1 protein (p.Leu844Pro). 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: 15060124, 29290338). ClinVar contains an entry for this variant (Variation ID: 68322). 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. This variant disrupts the p.Leu844 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10980545, 15060124, 27322474, 29290338). 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. -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 gene is constrained against variation (Z-score= 8.42 and pLI = 1), and missense variants are a common mechanism of disease (PMID: 20301288). The c.2531T>C (p.Leu844Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in individuals with neurofibromatosis type 1 (PMID: 15060124, 29290338). The c.2531T>C (p.Leu844Pro) variant is located in the cysteine-serine rich (CSR) domain, which is a known hotspot domain for pathogenic variations associated neurofibromatosis type 1 (PMID: 34230207, 29290338). Different amino acid changes at the same residue (p.Leu844Phe; p.Leu844His, p.Leu844Arg) have been previously reported in individuals with neurofibromatosis type 1 (PMID: 29290338, 9150739, 10980545). The c.2531T>C (p.Leu844Pro) variant is absent from the latest version of the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.2531T>C (p.Leu844Pro) is classified as Likely Pathogenic. -

Jun 05, 2019

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 26, 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: 24803665, 15060124, 29290338, 25486365, 2121369) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.93	P;D;.
Vest4		1.0
MutPred		0.92		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);.;
MVP		0.90
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.98

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: rs137854566; hg19: chr17-29556164; COSMIC: COSV62210964; COSMIC: COSV62210964;