VCV000224896.6 - ClinVar

NM_023110.3(FGFR1):c.1638C>A (p.Asn546Lys)

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.

(10)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_023110.3(FGFR1):c.1638C>A (p.Asn546Lys)

Variation ID: 224896 Accession: VCV000224896.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.23 8: 38417331 (GRCh38) [ NCBI UCSC ] 8: 38274849 (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	Aug 22, 2016	Oct 1, 2022
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_023110.3:c.1638C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075598.2:p.Asn546Lys	missense
NM_001174063.2:c.1632C>A	NP_001167534.1:p.Asn544Lys	missense
NM_001174064.2:c.1608C>A	NP_001167535.1:p.Asn536Lys	missense
NM_001174065.2:c.1632C>A	NP_001167536.1:p.Asn544Lys	missense
NM_001174066.2:c.1371C>A	NP_001167537.1:p.Asn457Lys	missense
NM_001174067.2:c.1731C>A	NP_001167538.1:p.Asn577Lys	missense
NM_001354367.2:c.1632C>A	NP_001341296.1:p.Asn544Lys	missense
NM_001354368.2:c.1359C>A	NP_001341297.1:p.Asn453Lys	missense
NM_001354369.2:c.1626C>A	NP_001341298.1:p.Asn542Lys	missense
NM_001354370.2:c.1365C>A	NP_001341299.1:p.Asn455Lys	missense
NM_015850.4:c.1632C>A	NP_056934.2:p.Asn544Lys	missense
NM_023105.3:c.1371C>A	NP_075593.1:p.Asn457Lys	missense
NM_023106.3:c.1365C>A	NP_075594.1:p.Asn455Lys	missense
NC_000008.11:g.38417331G>T
NC_000008.10:g.38274849G>T
NG_007729.1:g.56504C>A
LRG_993:g.56504C>A
LRG_993t1:c.1638C>A	LRG_993p1:p.Asn546Lys
	P11362:p.Asn546Lys

... more HGVS ... less HGVS

Protein change

N546K, N536K, N542K, N544K, N453K, N457K, N577K, N455K

Other names

Canonical SPDI

NC_000008.11:38417330:G:T

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

UniProtKB: P11362#VAR_075853 OMIM: 136350.0033 dbSNP: rs779707422 ClinGen: CA357830 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.
FGFR1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1003	1133

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.
Encephalocraniocutaneous lipomatosis	Pathogenic (4)	criteria provided, single submitter	-	RCV000210485.7
Medulloblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000439566.1
Neuroblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000428878.1
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422315.1
Brainstem glioma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000429528.1
Astrocytoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440238.1
Rosette-forming glioneuronal tumor	Pathogenic (1)	criteria provided, single submitter	-	RCV000487433.1

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 (-)	criteria provided, single submitter (Parsons' et. al 2016) Method: clinical testing	Rosette-forming glioneuronal tumor Affected status: yes Allele origin: somatic	Donald Williams Parsons Laboratory, Baylor College of Medicine Additional submitter: Sharon E. Plon Laboratory, Baylor College of Medicine Study: CSER-BASIC3 Accession: SCV000292258.2 First in ClinVar: Apr 28, 2017 Last updated: Apr 28, 2017 Comment: The exon 12 missense FGFR1 mutation identified (c.1638C>A; p.N546K) occurs within the kinase domain of the protein and is the most frequent somatic FGFR1 mutation … (more) The exon 12 missense FGFR1 mutation identified (c.1638C>A; p.N546K) occurs within the kinase domain of the protein and is the most frequent somatic FGFR1 mutation reported to date, having been found in both low and high grade gliomas and glioneuronal tumors (Forbes et al. 2015, Gessi et al. 2014). It has been shown to activate mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR signaling pathways (Turner et al. 2010, Zhang et al. 2013). (less)	Publications: PubMed (1) PubMed: 27626068 Clinical Features: Rosette-forming glioneuronal tumor (present) Zygosity: Single Heterozygote Age: 10-19 years Sex: female Ethnicity/Population group: African American Tissue: frozen tumor sample : Rosette-forming glioneuronal tumor of the fourth ventricle
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalocraniocutaneous lipomatosis Affected status: yes Allele origin: somatic	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001736964.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Pathogenic (Aug 11, 2016)	no assertion criteria provided Method: literature only	ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000266574.2 First in ClinVar: Apr 07, 2016 Last updated: Aug 22, 2016	Publications: PubMed (3) PubMed: 10766980‚ 23819449‚ 26942290 Comment on evidence: In 3 patients with encephalocraniocutaneous lipomatosis (ECCL; 613001), including a 15-year-old boy originally described by Nowaczyk et al. (2000) and a 5-year-old girl previously reported … (more) In 3 patients with encephalocraniocutaneous lipomatosis (ECCL; 613001), including a 15-year-old boy originally described by Nowaczyk et al. (2000) and a 5-year-old girl previously reported by Kupsik and Brandling-Bennett (2013), Bennett et al. (2016) identified mosaicism for a c.1638C-A transversion (c.1638C-A, NM_023110.2) in the FGFR1 gene, resulting in an asn546-to-lys (N546K) substitution in the first tyrosine kinase domain of the cytoplasmic kinase core. In the 15-year-old boy (LR13-278), the N546K substitution was identified in cultured fibroblasts from unaffected skin at an alternate allele fraction (AAF) of 35%, from a scalp nevus (42% AAF), and an eyelid dermoid (54% AAF). In the 5-year-old girl (LR14-261), the N546K mutation was present in cultured fibroblasts from a scalp nevus (55% AAF) but was not detected in saliva. In the third patient (IN_0039), a 17-month-old boy who had an unaffected monozygotic twin sib, N546K was identified in cultured fibroblasts from unaffected skin (23% AAF) and from a scalp lesion (33% AAF), but was not detected in the unaffected twin's blood. The N546K variant was not found in the Exome Variant Server, ExAC, or dbSNP databases. Bennett et al. (2016) stated that N546 is 1 of the 2 residues most commonly mutated among FGFR1 mutation-containing tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. The 15-year-old boy with the N546K mutation had been diagnosed with a tectal tumor. Functional analysis in patient fibroblasts demonstrated elevated autophosphorylation of FGFRs, the FGFR-dependent substrate FRS2 (607743), and the RAS (see 190020)-pathway components CRAF (164760) and ERK1 (601795)/ERK2 (176948), compared to wildtype. (less)
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neuroblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506366.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000425967:c.1731C>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Medulloblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506367.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000425967:c.1731C>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Brainstem glioma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506369.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000425967:c.1731C>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506368.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000425967:c.1731C>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Astrocytoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506370.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000425967:c.1731C>A
Likely pathogenic (May 25, 2017)	no assertion criteria provided Method: research	Encephalocraniocutaneous lipomatosis Affected status: yes Allele origin: unknown	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000882922.1 First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 26942290
not provided (-)	no classification provided Method: literature only	Encephalocraniocutaneous lipomatosis Affected status: unknown Allele origin: somatic	GeneReviews Accession: SCV002099545.2 First in ClinVar: Mar 02, 2022 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 26942290 BookShelf: NBK576966 BookShelf: NBK576966

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Encephalocraniocutaneous Lipomatosis.	Adam MP	-	2022	PMID: 35099867
Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle.	Lin FY	Cold Spring Harbor molecular case studies	2016	PMID: 27626068
Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.	Bennett JT	American journal of human genetics	2016	PMID: 26942290
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
An infant with an alopecic plaque on the scalp and ocular choristomas: case presentation. Diagnosis: Encephalocraniocutaneous lipomatosis (ECCL).	Kupsik M	Pediatric dermatology	2013	PMID: 23819449
Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis.	Nowaczyk MJ	American journal of medical genetics	2000	PMID: 10766980
http://docm.genome.wustl.edu/variants/ENST00000425967:c.1731C>A	-	-	-	-

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668850.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094157.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs779707422 ...

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 Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_023110.3(FGFR1):c.1638C>A (p.Asn546Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs779707422 ...