NM_001042492.3(NF1):c.1595T>C (p.Leu532Pro) AND Neurofibromatosis, type 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 12, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000168173.8

Allele description [Variation Report for NM_001042492.3(NF1):c.1595T>C (p.Leu532Pro)]

NM_001042492.3(NF1):c.1595T>C (p.Leu532Pro)

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.1595T>C (p.Leu532Pro)

HGVS:

NC_000017.11:g.31219072T>C
NG_009018.1:g.129096T>C
NM_000267.3:c.1595T>C
NM_001042492.3:c.1595T>CMANE SELECT
NM_001128147.3:c.1595T>C
NP_000258.1:p.Leu532Pro
NP_001035957.1:p.Leu532Pro
NP_001035957.1:p.Leu532Pro
NP_001121619.1:p.Leu532Pro
LRG_214t1:c.1595T>C
LRG_214t2:c.1595T>C
LRG_214:g.129096T>C
LRG_214p1:p.Leu532Pro
LRG_214p2:p.Leu532Pro
NC_000017.10:g.29546090T>C
NM_001042492.2:c.1595T>C
P21359:p.Leu532Pro

Protein change:

L532P

Links:

UniProtKB: P21359#VAR_032466; UniProtKB/Swiss-Prot: VAR_032466; dbSNP: rs199474737

NCBI 1000 Genomes Browser:

rs199474737

Molecular consequence:

NM_000267.3:c.1595T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.1595T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128147.3:c.1595T>C - 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
SCV000218836	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15060124, 28492532
SCV001479188	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218836

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 12, 2023)

germline

clinical testing

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

SCV001479188

Genome Diagnostics Laboratory, The Hospital for Sick Children

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 26, 2020)

germline

clinical testing

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

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

Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain.

Mattocks C, Baralle D, Tarpey P, ffrench-Constant C, Bobrow M, Whittaker J.

J Med Genet. 2004 Apr;41(4):e48. No abstract available.

PubMed [citation]

PMID:: 15060124
PMCID:: PMC1735749

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000218836.5

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

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 68302). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 15060124; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 532 of the NF1 protein (p.Leu532Pro).

#	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

From Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV001479188.1

#	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

Last Updated: Mar 5, 2024

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