VCV000016326.7 - ClinVar

NM_213647.3(FGFR4):c.1162G>A (p.Gly388Arg)

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.

(4)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_213647.3(FGFR4):c.1162G>A (p.Gly388Arg)

Variation ID: 16326 Accession: VCV000016326.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q35.2 5: 177093242 (GRCh38) [ NCBI UCSC ] 5: 176520243 (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 11, 2018	Oct 8, 2024	Oct 28, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_213647.3:c.1162G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_998812.1:p.Gly388Arg	missense
NM_001291980.2:c.1097+65G>A		intron variant
NM_001354984.2:c.1162G>A	NP_001341913.1:p.Gly388Arg	missense
NM_002011.5:c.1162G>A	NP_002002.3:p.Gly388Arg	missense
NM_022963.3:c.1058-90G>A		intron variant
NC_000005.10:g.177093242G>A
NC_000005.9:g.176520243G>A
NG_012067.1:g.11323G>A
	P22455:p.Gly388Arg

... more HGVS ... less HGVS

Protein change

G388R

Other names

FGFR4, GLY388ARG (rs351855)

Canonical SPDI

NC_000005.10:177093241:G:A

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.

0.29952 (A)

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

The Genome Aggregation Database (gnomAD) 0.26099

Trans-Omics for Precision Medicine (TOPMed) 0.26272

1000 Genomes Project 30x 0.29310

1000 Genomes Project 0.29952

Exome Aggregation Consortium (ExAC) 0.32098

The Genome Aggregation Database (gnomAD), exomes 0.32711

Links

ClinGen: CA126374 UniProtKB: P22455#VAR_014797 OMIM: 134935.0001 dbSNP: rs351855 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.
FGFR4		-	-	GRCh38 GRCh37	70	132

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.
Cancer progression and tumor cell motility	Pathogenic (1)	no assertion criteria provided	Feb 1, 2002	RCV000017723.29
See cases	Uncertain significance (1)	criteria provided, single submitter	Oct 17, 2019	RCV001196704.2
not specified	Benign (1)	criteria provided, single submitter	Oct 28, 2020	RCV001777142.1
FGFR4-related disorder	Benign (1)	no assertion criteria provided	Oct 17, 2019	RCV003974837.2

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.
Uncertain significance (Oct 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367335.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more) This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. (less) Clinical Features: Leukemia (present) , Breast carcinoma (present) , Stomach cancer (present) , Hodgkin lymphoma (present) , Neoplasm of brain (present)
Benign (Oct 28, 2020)	criteria provided, single submitter (Choudhury A et al. (Nature 2020)) Method: research	not specified Affected status: unknown Allele origin: germline	H3Africa Consortium Study: H3Africa Accession: SCV002014630.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021	Comment: While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.172, its frequency in African populations is >5%. This suggests that previous classifications of … (more) While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.172, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. (less)
Pathogenic (Feb 01, 2002)	no assertion criteria provided Method: literature only	CANCER PROGRESSION AND TUMOR CELL MOTILITY Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000038000.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 11, 2018	Publications: PubMed (2) PubMed: 11830541‚ 26675719 Comment on evidence: Bange et al. (2002) found a relationship between the gly388-to-arg substitution in FGFR4 and cancer progression and tumor cell motility. The arg388 allele was associated … (more) Bange et al. (2002) found a relationship between the gly388-to-arg substitution in FGFR4 and cancer progression and tumor cell motility. The arg388 allele was associated with metastasis and poor prognosis in breast cancer and in colon cancer. In a control group of 123 subjects, the frequencies of the gly/gly, gly/arg, and arg/arg genotypes were 45%, 49%, and 6%, respectively. Ulaganathan et al. (2015) noted that the FGFR4 SNP rs351855 (c.1162G-A, G388R), associated with cancer progression and poor prognosis, was found in the 1000 Genomes Project database at a minor allele frequency of 0.30 and was found in approximately 50% of patients with cancer (Bange et al., 2002). Ulaganathan et al. (2015) showed that substitution of the conserved glycine-388 residue to a charged arginine residue alters the transmembrane-spanning segment and exposes a membrane-proximal cytoplasmic STAT3 (102582)-binding site Y(390)-(P)XXQ(393). Ulaganathan et al. (2015) demonstrated that such membrane-proximal STAT3-binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently colocalize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 G385R (mouse homolog of human G388R) knockin mice and transgenic mouse models for breast and lung cancers, the authors validated the enhanced STAT3 signaling induced by the FGFR4 G388R variant in vivo. Ulaganathan et al. (2015) concluded that their findings elucidated the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggested that germline variants of cell surface molecules that recruit STAT3 to the inner cell membrane confer a significant risk for cancer prognosis and disease progression. (less)
Benign (Oct 17, 2019)	no assertion criteria provided Method: clinical testing	FGFR4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004799271.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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
Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site.	Ulaganathan VK	Nature	2015	PMID: 26675719
Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.	Bange J	Cancer research	2002	PMID: 11830541

Text-mined citations for rs351855 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_213647.3(FGFR4):c.1162G>A (p.Gly388Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs351855 ...