rs121918489

Positions:

• chr10-121517385-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000358487.10(FGFR2):​c.1018T>C​(p.Tyr340His) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y340C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 ENST00000358487.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.26

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000358487.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121517384-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 449398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 10-121517385-A-G is Pathogenic according to our data. Variant chr10-121517385-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517385-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1018T>C	p.Tyr340His	missense_variant	8/18	ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.1087+1297T>C		intron_variant		ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1018T>C	p.Tyr340His	missense_variant	8/18	1	NM_000141.5	ENSP00000351276	A2
FGFR2	ENST00000457416.7	c.1087+1297T>C		intron_variant		1	NM_022970.4	ENSP00000410294	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 20, 2023	Criteria applied: PM5_STR,PS4_MOD,PM1,PM2_SUP,PP1,PP3,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1994	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2024	Published functional studies demonstrate constitutive activation of FGFR2 measured as increased activity and covalent dimerization and ability to transform cells (PMID: 8755573); 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: 24411056, 29230096, 11781872, 35372644, 35455591, 23754559, 9521581, 24127277, 16418739, 7987400, 7607643, 32178948, 8755573) -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This missense change has been observed in individuals with FGFR2-related conditions, usually Crouzon syndrome (PMID: 7987400, 9521581, 16418739). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 340 of the FGFR2 protein (p.Tyr340His). ClinVar contains an entry for this variant (Variation ID: 13264). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 8755573). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PROVEAN	Uncertain	-3.9	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;D;.;.;.
Vest4		0.95
MutPred		0.99		.;.;Gain of sheet (P = 0.039);.;.;Gain of sheet (P = 0.039);.;.;
MVP		0.98
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918489; hg19: chr10-123276899;