NM_001042492.3(NF1):c.245C>T (p.Ser82Phe) AND Neurofibromatosis, type 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000659959.8

Allele description [Variation Report for NM_001042492.3(NF1):c.245C>T (p.Ser82Phe)]

NM_001042492.3(NF1):c.245C>T (p.Ser82Phe)

Gene:

NF1:neurofibromin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q11.2

Genomic location:

Preferred name:

NM_001042492.3(NF1):c.245C>T (p.Ser82Phe)

HGVS:

NC_000017.11:g.31159050C>T
NG_009018.1:g.69074C>T
NM_000267.3:c.245C>T
NM_001042492.3:c.245C>TMANE SELECT
NM_001128147.3:c.245C>T
NP_000258.1:p.Ser82Phe
NP_001035957.1:p.Ser82Phe
NP_001035957.1:p.Ser82Phe
NP_001121619.1:p.Ser82Phe
LRG_214t1:c.245C>T
LRG_214t2:c.245C>T
LRG_214:g.69074C>T
LRG_214p1:p.Ser82Phe
LRG_214p2:p.Ser82Phe
NC_000017.10:g.29486068C>T
NM_001042492.2:c.245C>T
P21359:p.Ser82Phe

Protein change:

S82F

Links:

UniProtKB: P21359#VAR_021730; UniProtKB/Swiss-Prot: VAR_021730; dbSNP: rs199474729

NCBI 1000 Genomes Browser:

rs199474729

Molecular consequence:

NM_000267.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128147.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neurofibromatosis, type 1 (NF1)
Synonyms:: NEUROFIBROMATOSIS, TYPE I; Recklinghausen's disease; Von Recklinghausen disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018975; MedGen: C0027831; Orphanet: 636; OMIM: 162200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000781866	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001479000	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001590554	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11857752, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000781866

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 1, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001479000

Genome Diagnostics Laboratory, The Hospital for Sick Children

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 26, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001590554

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 3, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas.

Kluwe L, Friedrich RE, Korf B, Fahsold R, Mautner VF.

Hum Mutat. 2002 Mar;19(3):309.

PubMed [citation]

PMID:: 11857752

See all PubMed Citations (3)

Details of each submission

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781866.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV001479000.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590554.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 82 of the NF1 protein (p.Ser82Phe). This variant is present in population databases (rs199474729, gnomAD 0.003%). This missense change has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 11857752; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68320). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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