VCV000547570.24 - ClinVar

NM_001042492.3(NF1):c.667T>C (p.Trp223Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.667T>C (p.Trp223Arg)

Variation ID: 547570 Accession: VCV000547570.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31181722 (GRCh38) [ NCBI UCSC ] 17: 29508740 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 9, 2018	Oct 20, 2024	Aug 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.667T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035957.1:p.Trp223Arg	missense
NM_000267.3:c.667T>C	NP_000258.1:p.Trp223Arg	missense
NM_001128147.3:c.667T>C	NP_001121619.1:p.Trp223Arg	missense
NC_000017.11:g.31181722T>C
NC_000017.10:g.29508740T>C
NG_009018.1:g.91746T>C
LRG_214:g.91746T>C
LRG_214t1:c.667T>C	LRG_214p1:p.Trp223Arg

... more HGVS ... less HGVS

Protein change

W223R

Other names

Canonical SPDI

NC_000017.11:31181721:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1555608740 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	14135	14574

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neurofibromatosis, type 1	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 23, 2023	RCV000659966.13
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV000680812.14

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781878.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Pathogenic (Oct 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV001479108.1 First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021
Likely pathogenic (Jun 17, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000808258.1 First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018	Comment: Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant … (more) Not observed in large population cohorts (Lek 2016); 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, 29566708, 25541118, 16944272, 27838393, 31370276) (less)
Likely pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002561594.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Likely pathogenic (Aug 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics, University of Parma Accession: SCV002567803.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Likely pathogenic (Dec 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579698.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM6, PS4_SUP, PM2_SUP, PP3, PP4	Number of individuals with the variant: 1 Sex: male
Pathogenic (Aug 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurofibromatosis, type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002231849.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16944272‚ 25541118‚ 29566708 Comment: This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 223 of the NF1 protein … (more) This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 223 of the NF1 protein (p.Trp223Arg). 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: 16944272, 25541118, 29566708). ClinVar contains an entry for this variant (Variation ID: 547570). 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. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004009768.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: NF1: PS1, PM2, PM6, PP3, PP4 Number of individuals with the variant: 1

Comment:

Not observed in large population cohorts (Lek 2016); 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, 29566708, 25541118, 16944272, 27838393, 31370276)

Comment:

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 223 of the NF1 protein (p.Trp223Arg). 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: 16944272, 25541118, 29566708). ClinVar contains an entry for this variant (Variation ID: 547570). 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. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Seizures in children with neurofibromatosis type 1: is neurofibromatosis type 1 enough?	Santoro C	Italian journal of pediatrics	2018	PMID: 29566708
[Phenotypic and genetic features in neurofibromatosis type 1 in children].	Duat Rodríguez A	Anales de pediatria (Barcelona, Spain : 2003)	2015	PMID: 25541118
Molecular diagnosis of neurofibromatosis type 1: 2 years experience.	Griffiths S	Familial cancer	2007	PMID: 16944272

Text-mined citations for rs1555608740 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.667T>C (p.Trp223Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555608740 ...