10-121496701-T-C
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000141.5(FGFR2):c.1694A>G(p.Glu565Gly) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E565A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000141.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_022970.4 | c.1697A>G | p.Glu566Gly | missense_variant | 13/18 | ENST00000457416.7 | |
FGFR2 | NM_000141.5 | c.1694A>G | p.Glu565Gly | missense_variant | 13/18 | ENST00000358487.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000457416.7 | c.1697A>G | p.Glu566Gly | missense_variant | 13/18 | 1 | NM_022970.4 | P4 | |
FGFR2 | ENST00000358487.10 | c.1694A>G | p.Glu565Gly | missense_variant | 13/18 | 1 | NM_000141.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
FGFR2-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 565 of the FGFR2 protein (p.Glu565Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pfeiffer syndrome (PMID: 11781872). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374823). 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. This variant disrupts the p.Glu565 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15523615, 18541976, 24127277). 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. - |
Pfeiffer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 17, 2016 | - - |
Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Dec 26, 2014 | - - |
Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0024623:Gastric cancer;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
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2022 | 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: 28166054, 23754559, 11781872, 23908597, 32139749) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at