17-31200513-T-C

Variant names:

• chr17-31200513-T-C
• rs201624827
• NM_001042492.3:c.980T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001042492.3(NF1):​c.980T>C​(p.Leu327Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L327F?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.37

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 17-31200513-T-C is Pathogenic according to our data. Variant chr17-31200513-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547576.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.980T>C	p.Leu327Pro	missense_variant	Exon 9 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.980T>C	p.Leu327Pro	missense_variant	Exon 9 of 57		NP_000258.1
NF1	NM_001128147.3	c.980T>C	p.Leu327Pro	missense_variant	Exon 9 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.980T>C	p.Leu327Pro	missense_variant	Exon 9 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Jan 20, 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 327 of the NF1 protein (p.Leu327Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 and/or NF1-Noonan syndrome (PMID: 18183640, 29685074, 36304179). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 547576). 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%. For these reasons, this variant has been classified as Pathogenic. -

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

- -

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

Mar 29, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L327P variant (also known as c.980T>C), located in coding exon 9 of the NF1 gene, results from a T to C substitution at nucleotide position 980. The leucine at codon 327 is replaced by proline, an amino acid with similar properties. This alteration has been determined to be the result of a de novo event in one individual in our laboratory. This variant has been reported in an individual with neurofibromatosis type 1 (Syrbe S et al. Klin Padiatr. 2007; 219:326-32). This variant is considered to be rare based on population 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 majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Dec 03, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.980T>C; p.Leu327Pro variant is published in the medical literature in one individual with a clinical diagnosis of NF1 (Syrbe 2007). Additionally, other variants in the same codon, p.Leu327Gln and p.Leu327Arg, are described in a gene-specific database (see link below). The p.Leu327Pro variant is not described in the ClinVar database, or in the general population-based databases, but is listed in the dbSNP variant database (rs201624827). The leucine at this position is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Link to NF1 database: https://databases.lovd.nl/shared/genes/NF1 Syrbe S et al. Neurofibromatosis type 1 and associated clinical abnormalities in 27 children. Klin Padiatr. 2007 Nov-Dec;219(6):326-32. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.5	M;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	.;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		1.0, 0.99
MutPred		0.90		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201624827; hg19: chr17-29527531;