10-121515280-T-C

Position:

• chr10-121515280-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1124A>G​(p.Tyr375Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar 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:12
• Conservation: PhyloP100: 7.94

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.931
• PP5: Variant 10-121515280-T-C is Pathogenic according to our data. Variant chr10-121515280-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121515280-T-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.1124A>G	p.Tyr375Cys	missense_variant	9/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1124A>G	p.Tyr375Cys	missense_variant	9/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1127A>G	p.Tyr376Cys	missense_variant	9/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1127A>G	p.Tyr376Cys	missense_variant	8/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1127A>G	p.Tyr376Cys	missense_variant	9/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.857A>G	p.Tyr286Cys	missense_variant	8/17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.788A>G	p.Tyr263Cys	missense_variant	6/15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.782A>G	p.Tyr261Cys	missense_variant	7/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.860A>G	p.Tyr287Cys	missense_variant	8/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.440A>G	p.Tyr147Cys	missense_variant	8/17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*171A>G		non_coding_transcript_exon_variant	8/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*171A>G		3_prime_UTR_variant	8/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beare-Stevenson cutis gyrata syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology	-	Recurrent pathogenic: RCV000762799 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 09, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 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: 12000365, 12900900, 23754559, 16531735, 25937001, 17525745, 19610084, 12145519, 27079505, 21397175, 17449949, 35050789, 32158469, 21479481, 8696350, 9545103, 25706251, 20856019) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 28, 2014	- -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the FGFR2 protein (p.Tyr375Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Beare-Stevenson cutis gyrata syndrome (PMID: 8696350, 12145519, 12900900, 16531735, 20856019, 21397175, 25706251, 25937001, 27079505). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13277). 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%. For these reasons, this variant has been classified as Pathogenic. -

FGFR2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The FGFR2 c.1124A>G variant is predicted to result in the amino acid substitution p.Tyr375Cys. This variant has been well documented to be pathogenic for Beare-Stevenson cutis gyrata syndrome (see for example Przylepa et al. 1996. PubMed ID: 8696350; Fonseca et al. 2008. PubMed ID: 21479481; Wenger et al. 2015. PMID: 25706251; Ron et al. 2016. PubMed ID: 27079505). This variant has also been identified as a de novo variant in an infant with a clinical diagnosis of Pfeiffer syndrome (Willig et al. 2015. PubMed ID: 25937001). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0038356:Neoplasm of stomach;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;.;T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	2.9	.;.;.;M;.;.;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D;D;.;D;.;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;.;D;.;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;T;T;D;T;D;T;D;D;D;D;D;D;.
Polyphen		1.0, 1.0, 0.93	.;D;.;D;.;D;.;.;.;.;P;D;.;.
Vest4		0.93
MutPred		0.81		.;.;.;Loss of disorder (P = 0.1004);.;.;.;Loss of disorder (P = 0.1004);.;.;.;.;.;.;
MVP		0.92
MPC		2.0
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.71
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121913478; hg19: chr10-123274794; COSMIC: COSV60640350; COSMIC: COSV60640350;