10-121517378-C-G

Position:

• chr10-121517378-C-G

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1025G>C​(p.Cys342Ser) 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. 11/18 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 Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C342F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.85

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 23 ACMG points.

• PS1: Transcript NM_000141.5 (FGFR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 8) in uniprot entity FGFR2_HUMAN there are 20 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 chr10-121517378-C-A is described in Lovd as [Pathogenic].
• 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). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. GenCC has associacion of the 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, 0.993
• PP5: Variant 10-121517378-C-G is Pathogenic according to our data. Variant chr10-121517378-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 374820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517378-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1025G>C	p.Cys342Ser	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.1025G>C	p.Cys342Ser	missense_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.758G>C	p.Cys253Ser	missense_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.341G>C	p.Cys114Ser	missense_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1304G>C		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1304G>C		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1304G>C		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2059G>C		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1304G>C		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1304G>C		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*72G>C		non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*72G>C		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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	FGFR2: PM1:Strong, PM2, PS2:Moderate, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2023	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: 23754559, 26362256, 24127277, 9586546, 12884424, 8644708, 9385368, 16418739, 34133757, 36316869, 26582918) -

FGFR2-related craniosynostosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The p.Cys342Ser variant substitutes the cysteine at amino acid position 342 with a serine in the Ig-like C2-type 3 domain of the FGFR2 protein. This variant has been reported in multiple unrelated individuals with FGFR2-related syndromes, including Pfeiffer syndrome (MIM: 101600) and Crouzon syndrome (MIM: 123500). Other variants at this position, including p.Cys342Tyr and p.Cys342Trp, have also been reported in affected individuals. In silico tools predict that the p.Cys342Ser variant is damaging. To our knowledge, functional studies have not been performed with the p.Cys342Ser variant, but functional studies using the p.Cys342Tyr showed a gain of function of effect (Eswarakumar et al., 2004). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 22, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 342 of the FGFR2 protein (p.Cys342Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with craniosynostosis syndromes including Pfeiffer or Crouzen syndromes (PMID: 8644708, 9586546, 12884424, 12884434, 24127277, 25271085, 26362256). ClinVar contains an entry for this variant (Variation ID: 374820). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Pfeiffer syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	research	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	Apr 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 13, 2023	The FGFR2 c.1025G>C variant is classified as Pathogenic (PS4, PS3_Moderate, PM1, PM2, PP4) The FGFR2 c.1025G>C variant is a single nucleotide change in exon 8/18 of the FGFR2 gene, which is predicted to change the amino acid cysteine at position 342 in the protein, to serine. This variant has been reported in at least 15 probands with a clinical presentation of Craniosynostosis/Pfeiffer syndrome (PMID# 9586546, 12884424, 24127277, 26362256, 9385368) (PS4) and is located in the conserved Cys342 amino acid where multiple changes to the same amino acid (p.C342R/G/F/W/Y) is reported in individuals with craniosynostosis (PM1). Well-established functional studies show a deleterious effect as a result of change to this conserved amino acid. A mouse model of the most common change to this amino acid (p.C342Y) reflected a craniosysnostosis phenotype. Biochemically these substitutions are considered 'functionally identical' (PMID#26362256) (PS3_moderate). The clinical features of this case are highly specific for FGFR2 and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). This variant is absent from population databases (PM2), has been reported in dbSNP (rs121918487), is reported HGMD as disease causing (CM960647) and is reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 374820). literature: PubMed: 8644708 -

FGFR2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2024

The FGFR2 c.1025G>C variant is predicted to result in the amino acid substitution p.Cys342Ser. This variant has been reported in multiple individuals with Pfeiffer syndrome and Crouzon syndrome (Table 2, Chun et al. 2003. PubMed ID: 12884424; Table 2, Roscioli et al. 2013. PubMed ID: 24127277). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Cys342Gly, p.Cys342Arg, p.Cys342Phe, p.Cys342Trp, and p.Cys342Tyr) have been reported in many individuals with Pfeiffer syndrome and Crouzon syndrome (Table 1, Meyers et al. 1996. PubMed ID: 8644708; Table 2, Cornejo-Roldan et al. 1999. PubMed ID: 10394936; Table 1, Paumard-Hernández et al. 2014. PubMed ID: 25271085). The c.1025G>C (p.Cys342Ser) variant is interpreted as pathogenic. -

Crouzon syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

- -

Jackson-Weiss syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 17, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;.;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	0.99	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;H;.;.
PROVEAN	Pathogenic	-7.8	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.98
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		0.98
MutPred		0.97		.;.;Gain of disorder (P = 0.0049);.;.;Gain of disorder (P = 0.0049);.;.;
MVP		0.95
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs121918487; hg19: chr10-123276892;