10-121517372-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000141.5(FGFR2):c.1031C>G(p.Ala344Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,120 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A344P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.93

Publications

18 publications found

Variant links:

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

FGFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr10-121517373-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1076383.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.976

PP5

Variant 10-121517372-G-C is Pathogenic according to our data. Variant chr10-121517372-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13269.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 link	c.1031C>G	p.Ala344Gly	missense_variant	Exon 8 of 18	ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4 link	c.1087+1310C>G		intron_variant	Intron 8 of 17	ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGFR2	ENST00000358487.10 link	c.1031C>G	p.Ala344Gly	missense_variant	Exon 8 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4 link	c.764C>G	p.Ala255Gly	missense_variant	Exon 7 of 17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5 link	c.347C>G	p.Ala116Gly	missense_variant	Exon 7 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5 link	n.*78C>G		non_coding_transcript_exon_variant	Exon 7 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5 link	n.*78C>G		3_prime_UTR_variant	Exon 7 of 17	1		ENSP00000474109.1
FGFR2	ENST00000457416.7 link	c.1087+1310C>G		intron_variant	Intron 8 of 17	1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000369056.5 link	c.1087+1310C>G		intron_variant	Intron 7 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7 link	c.1087+1310C>G		intron_variant	Intron 8 of 16	1		ENSP00000358054.3
FGFR2	ENST00000369061.8 link	c.749-2053C>G		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5 link	c.742+1310C>G		intron_variant	Intron 6 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7 link	c.820+1310C>G		intron_variant	Intron 7 of 16	2		ENSP00000353262.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

FGFR2-related craniosynostosis

Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 344 of the FGFR2 protein (p.Ala344Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 7874170). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13269). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FGFR2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala344 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8644708, 11556600, 22665975). 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.

Crouzon syndrome

Pathogenic:1

Aug 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Pfeiffer syndrome

Pathogenic:1

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75; 3Cnet: 0.40). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000013269 / PMID: 7874170) and a different missense change at the same codon (p.Ala344Pro / ClinVar ID: VCV001076383 / PMID: 8644708) have been previously reported to be associated with FGFR2 related disorder. The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 7581378, 7874170). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

FGFR2-related disorder

Pathogenic:1

Aug 10, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant results in a c.1031C>G (p.Ala344Gly) change in an alternate transcript (ENST00000346997, NM_000141.5). The FGFR2 gene is constrained against variation (Z-score= 4.45 and pLI = 1), and missense variants are a common mechanism of disease (PMID: 20301628, 31145570). The c.1087+1310C>G variant affects a weakly conserved amino acid; however, in silico analyses predict a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in patients with FGFR2-related disorders (PMID: 7874170). A different amino acid change at the same residue (p.Ala344Pro) has been previously reported in individuals with FGFR2-related disorders (PMID: 8644708, 11556600, 22665975). The c.1087+1310C>G variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.00006% (1/1613958) and thus is presumed to be rare. Based on the available evidence, this c.1087+1310C>G is classified as Pathogenic.

Jackson-Weiss syndrome

Pathogenic:1

Aug 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;D;.;.;.;T;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

0.0

.;.;L;.;.;L;.;.

PhyloP100

9.9

PROVEAN

Uncertain

-3.0

D;.;D;.;D;D;.;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;.;D;.;D;D;.;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D;.

Vest4

0.90

ClinPred

0.94

GERP RS

5.9

Varity_R

0.78

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over