chr10-121520048-C-G

Variant names:

• chr10-121520048-C-G
• rs121918499
• NM_022970.4:c.870G>C

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_022970.4(FGFR2):​c.870G>C​(p.Trp290Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W290G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_022970.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.90
• Publications: 86 publications found

Genes affected

FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

FGFR2 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 27 ACMG points.

• PS1: Transcript NM_022970.4 (FGFR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_022970.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121520050-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.3638 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-121520048-C-G is Pathogenic according to our data. Variant chr10-121520048-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.870G>C	p.Trp290Cys	missense	Exon 7 of 18	NP_075259.4
	FGFR2	NM_000141.5	MANE Select	c.870G>C	p.Trp290Cys	missense	Exon 7 of 18	NP_000132.3
	FGFR2	NM_001441087.1		c.870G>C	p.Trp290Cys	missense	Exon 7 of 18	NP_001428016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.870G>C	p.Trp290Cys	missense	Exon 7 of 18	ENSP00000410294.2
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.870G>C	p.Trp290Cys	missense	Exon 7 of 18	ENSP00000351276.6
	FGFR2	ENST00000369056.5	TSL:1	c.870G>C	p.Trp290Cys	missense	Exon 6 of 17	ENSP00000358052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:3

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 17, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

May 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 29620724, 16955501, 30355600, 30132994, 24656465, 22965899, 18049087, 25103625, 36316724, 23754559, 27535533, 29230096, 9300656, 27683237, 9150725, 11380927, 24411056, 27228464, 23786770, 15565658, 24127277)

Mar 24, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the FGFR2 gene demonstrated a sequence change, c.870G>C, in exon 7 that results in an amino acid change, p.Trp290Cys. The p.Trp290Cys change affects a highly conserved amino acid residue located in a domain of the FGFR2 protein that is known to be functional. The p.Trp290Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, and REVEL). This sequence change has previously been described in several individuals with Pfeiffer syndrome (PMID: 9150725, 11380927, 24411056, 30132994, 15565658, and 16955501). Same amino acid change with a different nucleotide substitution (c.870G>T, p.Try290Cys) has also been reported in association with craniosynostosis syndromes and has been determined to be pathogenic (PMID: 9475591, 24036790, 18618990, and 27683237). This sequence change has not been described in population databases such as ExAC and gnomAD. These collective evidences indicate that this sequence change is pathogenic.

Aural atresia, congenital Pathogenic:1

Jan 23, 2020

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.870G>C variant within exon 7 is a recurrent change that has previously been reported in multiple individuals with Pfeiffer syndrome (PMID: 9150725, 11380927, 15565658, 16955501, 24411056, 27228464). The variant is absent from population databases (GnomAD). Other variants (c.870G>T) resulting in the same p.W290C protein change, as well as other amino acid substitutions at position 290, have been reported in individuals with craniosynostosis. Multiple in silico tools predict that the c.870G>C variant has a deleterious effect (DANN, DEOGEN2, EIGEN, FATHMM-MKL, M CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT). The p.W290C pathogenic variant has been most often observed in patients with a severe presentation who carry a clinical diagnosis of Pfeiffer syndrome type 2 or 3. Common phenotypic features include multisuture craniosynostosis, tracheal cartilaginous sleeve, severe ocular proptosis, elbow synostosis, intestinal malrotation, and short stature. Given the severity of the clinical presentation associated with the FGFR2 p.W290C variant, an aggressive surgical approach has been recommended (PMID: 29915381).

FGFR2-related disorder Pathogenic:1

Dec 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FGFR2 c.870G>C variant is predicted to result in the amino acid substitution p.Trp290Cys. This variant has been well documented to be causative for Pfeiffer syndrome (see for example Nazzaro et al. 2004. PubMed ID: 15565658; Oliveira et al. 2006. PubMed ID: 16955501; Chen et al. 2013. PubMed ID: 24411056; Wenger et al. 2017. PubMed ID: 27228464). In addition, alternate nucleotide changes affecting the same amino acid have been reported to be pathogenic for Pfeiffer syndrome or syndromic craniosynostosis (Ohishi et al. 2017. PubMed ID: 27683237; Saliba et al. 2018. PubMed ID: 29436723; Zhang et al. 2019. PubMed ID: 30692697; Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.98		Loss of sheet (P = 0.0817)
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918499; hg19: chr10-123279562; COSMIC: COSV60643917; COSMIC: COSV60643917;