10-121496701-T-G

Variant names:

• chr10-121496701-T-G
• rs121918506
• NM_000141.5:c.1694A>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1694A>C​(p.Glu565Ala) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E565G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.00
• Publications: 80 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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121496701-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374823.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: 4.4365 (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, 0.992
• PP5: Variant 10-121496701-T-G is Pathogenic according to our data. Variant chr10-121496701-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1694A>C	p.Glu565Ala	missense_variant	Exon 13 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1694A>C	p.Glu565Ala	missense_variant	Exon 13 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1697A>C	p.Glu566Ala	missense_variant	Exon 13 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1697A>C	p.Glu566Ala	missense_variant	Exon 12 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1697A>C	p.Glu566Ala	missense_variant	Exon 13 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1427A>C	p.Glu476Ala	missense_variant	Exon 12 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1358A>C	p.Glu453Ala	missense_variant	Exon 10 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1352A>C	p.Glu451Ala	missense_variant	Exon 11 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1430A>C	p.Glu477Ala	missense_variant	Exon 12 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1010A>C	p.Glu337Ala	missense_variant	Exon 12 of 17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.470A>C	p.Glu157Ala	missense_variant	Exon 5 of 9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*741A>C		non_coding_transcript_exon_variant	Exon 12 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*741A>C		3_prime_UTR_variant	Exon 12 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:4

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013294). A different missense change at the same codon (p.Glu565Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000374823). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 16, 2020

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 17, 2016

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

FGFR2-related craniosynostosis Pathogenic:1

Nov 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 565 of the FGFR2 protein (p.Glu565Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 15523615, 18541976, 24127277). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13294). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

FGFR2-related disorder Pathogenic:1

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGFR2 c.1694A>C variant is predicted to result in the amino acid substitution p.Glu565Ala. This variant has been reported in individuals with Pfeiffer syndrome (arisen de novo, Zankl et al. 2004. PubMed ID: 15523615; Freeman et al. 2008. PubMed ID: 18541976; Table S2, Wang et al. 2021. PubMed ID: 33502061) as well as an individual with Crouzon syndrome (Roscioli et al. 2013. PubMed ID: 24127277). In vitro functional studies demonstrate that expression of this variant results in a gain of function by constitutively activating the kinase activity of FGFR2 (Chen et al. 2007. PubMed ID: 17803937). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported by several laboratories as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13294/). Additionally, a different missense change impacting the same amino acid (p.Glu565Gly) has been reported to segregate with disease in a family with Pfeiffer syndrome (Kan et al. 2002. PubMed ID: 11781872), supporting the evidence that this amino acid may be important for FGFR2 function. Taken together, the p.Glu565Ala variant is interpreted as pathogenic. -

not provided Pathogenic:1

Oct 16, 2023

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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18541976, 17803937, 15523615, 31911531, 34250419, 33218975, 24127277, 33731768, 33502061) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;D;.;.;.;D;D;.;T;.;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.010	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.99, 1.0, 0.96, 1.0, 1.0	.;D;.;D;.;D;.;.;.;.;.;.;D;D;.;.
Vest4		0.97
MutPred		0.97		.;.;.;Loss of ubiquitination at K569 (P = 0.0468);.;.;.;.;.;.;Loss of ubiquitination at K569 (P = 0.0468);.;.;.;.;.;
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918506; hg19: chr10-123256215;