VCV002202644.3 - ClinVar

NM_000141.5(FGFR2):c.1274G>A (p.Arg425Gln)

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.

(2)

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
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000141.5(FGFR2):c.1274G>A (p.Arg425Gln)

Variation ID: 2202644 Accession: VCV002202644.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q26.13 10: 121515130 (GRCh38) [ NCBI UCSC ] 10: 123274644 (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	Feb 8, 2023	Feb 14, 2024	Feb 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000141.5:c.1274G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000132.3:p.Arg425Gln	missense
NM_022970.4:c.1277G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075259.4:p.Arg426Gln	missense
NM_001144913.1:c.1277G>A	NP_001138385.1:p.Arg426Gln	missense
NM_001144914.1:c.938G>A	NP_001138386.1:p.Arg313Gln	missense
NM_001144915.2:c.1007G>A	NP_001138387.1:p.Arg336Gln	missense
NM_001144916.2:c.929G>A	NP_001138388.1:p.Arg310Gln	missense
NM_001144917.2:c.939+4849G>A		intron variant
NM_001144918.2:c.929G>A	NP_001138390.1:p.Arg310Gln	missense
NM_001144919.2:c.1010G>A	NP_001138391.1:p.Arg337Gln	missense
NM_001320654.2:c.590G>A	NP_001307583.1:p.Arg197Gln	missense
NM_001320658.2:c.1274G>A	NP_001307587.1:p.Arg425Gln	missense
NM_022969.1:c.1277G>A	NP_075258.1:p.Arg426Gln	missense
NM_023029.2:c.1007G>A	NP_075418.1:p.Arg336Gln	missense
NR_073009.2:n.1710G>A		non-coding transcript variant
NC_000010.11:g.121515130C>T
NC_000010.10:g.123274644C>T
NG_012449.2:g.88329G>A
LRG_994:g.88329G>A
LRG_994t1:c.1274G>A	LRG_994p1:p.Arg425Gln
LRG_994t2:c.1277G>A	LRG_994p2:p.Arg426Gln

... more HGVS ... less HGVS

Protein change

R310Q, R336Q, R426Q, R313Q, R197Q, R337Q, R425Q

Other names

Canonical SPDI

NC_000010.11:121515129:C: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

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.
FGFR2		-	-	GRCh38 GRCh37	760	814

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.
FGFR2-related craniosynostosis	Uncertain significance (1)	criteria provided, single submitter	Jun 22, 2022	RCV002664133.3
Autosomal dominant syndrome including deafness	Likely pathogenic (1)	criteria provided, single submitter	Feb 28, 2023	RCV003155519.1

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.
Likely pathogenic (Feb 28, 2023)	criteria provided, single submitter (Li et al. (Genet Med. 2022)) Method: research	Autosomal dominant syndrome including deafness Affected status: yes Allele origin: unknown	King Laboratory, University of Washington Accession: SCV003844130.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (1) PubMed: 36633841 Comment: This variant occurred in heterozygosity in a patient with multiple congenital anomalies including lateral facial clefting, ophthalmologic abnormalities including glaucoma, tetralogy of Fallot, scoliosis, neurologic … (more) This variant occurred in heterozygosity in a patient with multiple congenital anomalies including lateral facial clefting, ophthalmologic abnormalities including glaucoma, tetralogy of Fallot, scoliosis, neurologic abnormalities including Dandy-Walker formation, and bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family history is unknown. This variant is a missense at a highly conserved site in the ligand binding region of the FGFR2 protein and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has not been reported to ClinVar. Based on consistently predicted functional effect and goodness of fit of genotype to phenotype we conclude that this variant is likely pathogenic. (less)
Uncertain significance (Jun 22, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	FGFR2-related craniosynostosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003522523.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FGFR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 425 of the FGFR2 protein (p.Arg425Gln). (less)

Comment:

This variant occurred in heterozygosity in a patient with multiple congenital anomalies including lateral facial clefting, ophthalmologic abnormalities including glaucoma, tetralogy of Fallot, scoliosis, neurologic abnormalities including Dandy-Walker formation, and bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family history is unknown. This variant is a missense at a highly conserved site in the ligand binding region of the FGFR2 protein and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has not been reported to ClinVar. Based on consistently predicted functional effect and goodness of fit of genotype to phenotype we conclude that this variant is likely pathogenic.

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FGFR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 425 of the FGFR2 protein (p.Arg425Gln).

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
Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.	Carlson RJ	JAMA otolaryngology-- head & neck surgery	2023	PMID: 36633841

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000141.5(FGFR2):c.1274G>A (p.Arg425Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...