17-31181482-T-G

Variant names:

• chr17-31181482-T-G
• rs199474756
• NM_001042492.3:c.647T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001042492.3(NF1):​c.647T>G​(p.Leu216Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L216P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.04
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 25 uncertain 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 chr17-31181482-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 68360.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 17-31181482-T-G is Pathogenic according to our data. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671. Variant chr17-31181482-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 648671.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.647T>G	p.Leu216Arg	missense_variant	Exon 6 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.647T>G	p.Leu216Arg	missense_variant	Exon 6 of 57		NP_000258.1
NF1	NM_001128147.3	c.647T>G	p.Leu216Arg	missense_variant	Exon 6 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.647T>G	p.Leu216Arg	missense_variant	Exon 6 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jul 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L216R variant (also known as c.647T>G), located in coding exon 6 of the NF1 gene, results from a T to G substitution at nucleotide position 647. The leucine at codon 216 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with neurofibromatosis type 1 (Palma Milla C et al. Ann Hum Genet, 2018 Nov;82:425-436; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a modest decrease in structural stability (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Neurofibromatosis, type 1 Uncertain:1

Nov 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with arginine at codon 216 of the NF1 protein (p.Leu216Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu216 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10712197, 17726231, 27617404), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.
PhyloP100		7.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	.;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.99, 0.99
MutPred		0.66		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);.;
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.025	Neutral
Varity_R		0.89
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199474756; hg19: chr17-29508500;