NM_000141.5:c.1576A>G

Variant names:

• chr10-121498591-T-C
• rs121918507
• NM_000141.5:c.1576A>G

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.1576A>G​(p.Lys526Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.01

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 13 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, 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, 0.876
• PP5: Variant 10-121498591-T-C is Pathogenic according to our data. Variant chr10-121498591-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13295.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.1576A>G	p.Lys526Glu	missense_variant	Exon 12 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1576A>G	p.Lys526Glu	missense_variant	Exon 12 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1579A>G	p.Lys527Glu	missense_variant	Exon 12 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1579A>G	p.Lys527Glu	missense_variant	Exon 11 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1579A>G	p.Lys527Glu	missense_variant	Exon 12 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1309A>G	p.Lys437Glu	missense_variant	Exon 11 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1240A>G	p.Lys414Glu	missense_variant	Exon 9 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1234A>G	p.Lys412Glu	missense_variant	Exon 10 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1312A>G	p.Lys438Glu	missense_variant	Exon 11 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.892A>G	p.Lys298Glu	missense_variant	Exon 11 of 17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.352A>G	p.Lys118Glu	missense_variant	Exon 4 of 9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*623A>G		non_coding_transcript_exon_variant	Exon 11 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*623A>G		3_prime_UTR_variant	Exon 11 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:1

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 526 of the FGFR2 protein (p.Lys526Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FGFR2-related conditions (PMID: 15523492, 16061565; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13295). 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. -

Crouzon syndrome Pathogenic:1

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial scaphocephaly syndrome, McGillivray type Pathogenic:1

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pfeiffer syndrome Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: increased activation of the FGFR2 kinase (PMID: 17803937); 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: 16061565, 17803937, 15523492) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;.;D;.;.;.;D;D;.;T;.;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.00020	T
MutationAssessor	Benign	0.19	.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.12, 0.73, 0.071, 0.0020, 0.68	.;B;.;P;.;B;.;.;.;.;.;.;B;P;.;.
Vest4		0.79
MutPred		0.76		.;.;.;Loss of ubiquitination at K526 (P = 0.0087);.;.;.;.;.;.;Loss of ubiquitination at K526 (P = 0.0087);.;.;.;.;.;
MVP		0.94
MPC		2.1
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.76

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: rs121918507; hg19: chr10-123258105;