10-121517342-G-C

Position:

• chr10-121517342-G-C

Variant summary

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

The NM_000141.5(FGFR2):​c.1061C>G​(p.Ser354Cys) 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. S354Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.93

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a strand (size 11) in uniprot entity FGFR2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.983
• PP5: Variant 10-121517342-G-C is Pathogenic according to our data. Variant chr10-121517342-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517342-G-C is described in Lovd as [Pathogenic]. Variant chr10-121517342-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1061C>G	p.Ser354Cys	missense_variant	8/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1061C>G	p.Ser354Cys	missense_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.794C>G	p.Ser265Cys	missense_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.377C>G	p.Ser126Cys	missense_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1340C>G		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1340C>G		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1340C>G		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2023C>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1340C>G		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1340C>G		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*108C>G		non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*108C>G		3_prime_UTR_variant	7/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jun 03, 2022	PM1, PM2, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2024	Published functional studies demonstrate the variant increases transactivation as compared to the wildtype (PMID: 8755573, 23913723); 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: 11173845, 16844695, 27028366, 11781872, 11711827, 32178948, 23754559, 7987400, 25271085, 17693524, 8528214, 24127277, 16418739, 23913723, 7581378, 24509851, 29230096, 8556306, 16360853, 7655462, 31446701, 32956303, 36478645, 35591945, 35455591, 35275860, 8755573) -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser354Phe, p.Ser354Tyr amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been observed in individuals with FGFR2-related conditions (PMID: 11173845, 12884424, 16418739), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 8755573). 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. ClinVar contains an entry for this variant (Variation ID: 13265). This variant is also known as c.1073C>G (p.Ser354Cys). This missense change has been observed in individual(s) with Crouzon syndrome (PMID: 7655462, 7989400, 8528214, 11173845, 11781872, 17693524, 24127277, 25271085, 27028366). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 354 of the FGFR2 protein (p.Ser354Cys). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2017

Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PM1,PM2,PM5,PP2,PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;.;D;.;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.0	.;.;M;.;.;M;.;.
PROVEAN	Uncertain	-3.5	D;.;D;.;D;D;.;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;D;.;.;.
Vest4		0.60
MutPred		0.98		.;.;Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);.;.;
MVP		0.88
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs121918490; hg19: chr10-123276856;