rs121918489
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000358487.10(FGFR2):c.1018T>C(p.Tyr340His) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y340C) has been classified as Pathogenic.
Frequency
Consequence
ENST00000358487.10 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGFR2 | NM_000141.5 | c.1018T>C | p.Tyr340His | missense_variant | 8/18 | ENST00000358487.10 | NP_000132.3 | |
FGFR2 | NM_022970.4 | c.1087+1297T>C | intron_variant | ENST00000457416.7 | NP_075259.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000358487.10 | c.1018T>C | p.Tyr340His | missense_variant | 8/18 | 1 | NM_000141.5 | ENSP00000351276 | A2 | |
FGFR2 | ENST00000457416.7 | c.1087+1297T>C | intron_variant | 1 | NM_022970.4 | ENSP00000410294 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Crouzon syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 20, 2023 | Criteria applied: PM5_STR,PS4_MOD,PM1,PM2_SUP,PP1,PP3,PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 17, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1994 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2024 | Published functional studies demonstrate constitutive activation of FGFR2 measured as increased activity and covalent dimerization and ability to transform cells (PMID: 8755573); 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: 24411056, 29230096, 11781872, 35372644, 35455591, 23754559, 9521581, 24127277, 16418739, 7987400, 7607643, 32178948, 8755573) - |
FGFR2-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 14, 2023 | This missense change has been observed in individuals with FGFR2-related conditions, usually Crouzon syndrome (PMID: 7987400, 9521581, 16418739). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 340 of the FGFR2 protein (p.Tyr340His). ClinVar contains an entry for this variant (Variation ID: 13264). 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. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 8755573). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at