chr10-121565500-T-C

Variant names:

• chr10-121565500-T-C
• rs1434545235
• NM_000141.5:c.314A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.314A>G​(p.Tyr105Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.24
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 10-121565500-T-C is Pathogenic according to our data. Variant chr10-121565500-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.314A>G	p.Tyr105Cys	missense_variant	Exon 2 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 17	1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.314A>G	p.Tyr105Cys	missense_variant	Exon 2 of 15	1		ENSP00000358057.4
FGFR2	ENST00000613048.4	c.110-921A>G		intron_variant	Intron 2 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.110-14041A>G		intron_variant	Intron 2 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.110-921A>G		intron_variant	Intron 2 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.110-14041A>G		intron_variant	Intron 2 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251352 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:3

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Strong+PP2+PP1+PS4_Moderate+PM6 -

Feb 02, 2022

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr105Cys variant is a recurrent pathogenic variant that has been reported in both the medical literature and patient databases among individuals with craniosynostosis and Crouzon syndrome (MIM #123500) (PMID: 8946174 and others). The p.Tyr105Cys variant replaces a tyrosine residue at amino acid position 105 with a cysteine in the immunoglobulin-like domain of the FGFR2 protein. This variant is present at an a very low frequency in a database of the general population (1 of 251,352 alleles, gnomAD v.2.1.1). Typically, FGFR2-related craniosynostosis variants are activating, although functional validation has not been performed to our knowledge for this variant. The FGFR2 p.Tyr105Cys variant has been found to be a de novo change in some individuals, and has also been demonstrated to segregate with the phenotype in families with multiple affected members (PMID: 16418739). -

Jan 12, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS4,PM1,PM2,PP1,PP3,PP5 -

not provided Pathogenic:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a 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: 16418739, 25425289, 34169787, 8946174, 27928320, 11781872, 24127277, 23754559, 34538793) -

FGFR2-related craniosynostosis Pathogenic:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 105 of the FGFR2 protein (p.Tyr105Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Crouzon syndrome (PMID: 1641873, 8946174, 11781872, 24127277; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449024). 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. -

Inborn genetic diseases Pathogenic:1

Nov 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314A>G (p.Y105C) alteration is located in exon 3 (coding exon 2) of the FGFR2 gene. This alteration results from an A to G substitution at nucleotide position 314, causing the tyrosine (Y) at amino acid position 105 to be replaced by a cysteine (C). for FGFR2-related craniosynostosis disorders; however, its clinical significance for FGFR2-related lacrimoauriculodentodigital syndrome is uncertain. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as heterozygous in individuals with features consistent with FGFR2-related craniosynostosis disorders or suspected to have Crouzon syndrome; in at least one individual, it was determined to be a de novo variant (Pulleyn, 1996; Kan, 2002; Lajeunie, 2006; Roscioli; 2013; Timberlake, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Bent bone dysplasia syndrome 1 Pathogenic:1

Aug 09, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PP3 -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Acrocephalosyndactyly type I Pathogenic:1

Dec 25, 2024

Obstetrics Unit, Tongji Hospital, Huazhong University of Science and Technology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFR2:NM_000141.5:exon3:c.314A>G:p.Y105C variant: possibly pathogenic (PS2+PS4_Moderate+PP1+PP3+PM2_Supporting) Strong pathogenicity evidence PS2: The literature reports a total of 1 patient in whom this variant was detected as de novo [PMID:11781872]; Moderate pathogenicity evidence PS4_Moderate: the literature reports that the variant was detected in a total of 6-14 patients [PMID:11781872]; Moderate pathogenicity evidence PS2: the literature reports that the variant was detected in a total of 1 patient [PMID:11781872]. [PMID:8946174;24127277;34538793;16418739;11781872;34169787]; Supports evidence of pathogenicity PP1: The literature reports that this variant is co-segregating with disease in multiple affected family members [PMID:24127277]; Support for pathogenicity evidence PP3: Predicted by multiple statistical methods (REVEL), the results show that the variant causes deleterious effects on the gene or gene product; Evidence in favor of pathogenicity PM2_Supporting: the variant is not found in the reference population Thousand Genomes (1000G), and the Human Exome Database (ExAC), and has a frequency of 2.89084e-05 in the Population Genome Mutation Frequency Database (gnomAD); The known variant was assessed as P in the ClinVar database; the known variant was assessed as DM in the HGMD database [PMID:8946174;23754559;24127277;34169787;34538793]; Mutations in the gene FGFR2 (OMIM:176943) cause Apert syndrome (OMIM:101200) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;D;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;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;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;H;H;.;H;H;H;H
PhyloP100		7.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;D;.;.
Vest4		0.98
MutPred		0.96		Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);
MVP		0.96
MPC		0.93
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1434545235; hg19: chr10-123325014;