10-121517391-C-G

Variant names:

• chr10-121517391-C-G
• rs1057519043
• NM_000141.5:c.1012G>C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1012G>C​(p.Gly338Arg) 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. 12/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.85

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 17 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
• 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, 0.991
• PP5: Variant 10-121517391-C-G is Pathogenic according to our data. Variant chr10-121517391-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 374816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517391-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1012G>C	p.Gly338Arg	missense_variant	Exon 8 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1012G>C	p.Gly338Arg	missense_variant	Exon 8 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.745G>C	p.Gly249Arg	missense_variant	Exon 7 of 17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.328G>C	p.Gly110Arg	missense_variant	Exon 7 of 17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1291G>C		intron_variant	Intron 8 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1291G>C		intron_variant	Intron 7 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1291G>C		intron_variant	Intron 8 of 16	1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2072G>C		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1291G>C		intron_variant	Intron 6 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1291G>C		intron_variant	Intron 7 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*59G>C		non_coding_transcript_exon_variant	Exon 7 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*59G>C		3_prime_UTR_variant	Exon 7 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:2

Sep 17, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR2-related disorders (PMIDs: 29848297, 32879300, 27323706). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance has only been reported in one family with ectrodactyly and acinar dysplasia (PMID: 27323706). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0219 - This variant is non-coding in an alternative transcript, but is coding in the ClinVar predominant transcript. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.(Gly338Glu) and p.(Gly338Tyr) variants have been observed in several individuals with Crouzon syndrome (ClinVar, PMIDs: 24127277, 11870239). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with Crouzon syndrome (ClinVar, PMIDs: 29848297, 7581378, 12477974, 16418739, 11781872, 9677057). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

FGFR2-related craniosynostosis Pathogenic:1

May 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). The p.Gly338 amino acid residue in FGFR2 has been determined to be clinically significant (PMID: 24127277, 11870239). This suggests that variants that disrupt this residue are likely to be causative of disease . For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals and families with Crouzon syndrome (PMID: 7581378, 29037998, 12477974, 16418739, 11781872, 9677057). ClinVar contains an entry for this variant (Variation ID: 374816). This sequence change replaces glycine with arginine at codon 338 of the FGFR2 protein (p.Gly338Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). -

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	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	.;.;H;.;.;H;.;.
PROVEAN	Pathogenic	-6.3	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	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		0.93		.;.;Gain of solvent accessibility (P = 0.1319);.;.;Gain of solvent accessibility (P = 0.1319);.;.;
MVP		0.97
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1057519043; hg19: chr10-123276905;