10-121517379-A-C

Position:

• chr10-121517379-A-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.1024T>G​(p.Cys342Gly) 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 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:4
• 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]

FGFR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• 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). 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, 0.994
• PP5: Variant 10-121517379-A-C is Pathogenic according to our data. Variant chr10-121517379-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 374818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517379-A-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.1024T>G	p.Cys342Gly	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.1024T>G	p.Cys342Gly	missense_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.757T>G	p.Cys253Gly	missense_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.340T>G	p.Cys114Gly	missense_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1303T>G		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1303T>G		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1303T>G		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2060T>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1303T>G		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1303T>G		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*71T>G		non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*71T>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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 342 of the FGFR2 protein (p.Cys342Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pfeiffer syndrome (PMID: 10394936, 31754721). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374818). 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.Cy342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8644708, 9586546, 12884424, 12884434, 24127277, 25271085, 26362256). 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:1

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:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2020

Variants altering the two critical cysteine residues 278 and 342 account for 60% of all pathogenic variants observed in (Robin et al., 2011); Cys342 variants have a gain-of-function effect; they cause abnormal dimerization and dimer structure resulting in FGFR2 activation, aberrant cell growth and blocking of cellular differentiation (Mansukhani et al., 2000); experimental mice models for C342Y have demonstrated significant defects in skull development (Holmes et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31754721, 10394936, 23754559) -

FGFR2-related syndromic and non-syndromic craniosynostoses Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 19, 2019

The FGFR2 c.1024T>G (p.Cys342Gly) variant is a missense variant occurring at an established mutational hotspot within the FGFR2 gene. The p.Cys342Gly variant has been reported in one study, in which it is reported in a heterozygous state in two unrelated individuals with clinical diagnoses of Pfeiffer syndrome. In one family the p.Cys342Gly variant was shown to be absent from both parents, consistent with a de novo occurrence (Cornejo-Roldan et al. 1999). Additionally, at least six variants resulting in different missense variants at the Cys342 residue have been reported in literature in individuals with clinical diagnoses including Pfeiffer, Crouzon and Jackson-Weiss syndromes (Park et al. 1995; Cornejo-Roldan et al. 1999; Lajeunie et al. 2006; Li et al. 2016). The p.Cys342Gly variant was absent from 100 control subjects and is not found in the Genome Aggregation Database. In vitro analysis in NIH 3T3 cell found variants that alter the Cys342 residue are associated with increased tyrosine kinase activity and aberrant generation of disulfide-bonded dimers (Galvin et al. 1996). The Cys342 residue is highly conserved and located in the Ig-III domain (Li et al. 2016). Based on the collective evidence, the p.Cys342Gly variant is classified as pathogenic for FGFR2-related syndromic and non-syndromic craniosynostoses. -

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	32
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	0.63	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	-9.3	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	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		0.98		.;.;Loss of stability (P = 0.0088);.;.;Loss of stability (P = 0.0088);.;.;
MVP		0.96
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918488; hg19: chr10-123276893;