rs79184941
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP2BS2
The NM_000141.5(FGFR2):c.755C>T(p.Ser252Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,612,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252W) has been classified as Pathogenic.
Frequency
Consequence
NM_000141.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_022970.4 | c.755C>T | p.Ser252Leu | missense_variant | 7/18 | ENST00000457416.7 | |
FGFR2 | NM_000141.5 | c.755C>T | p.Ser252Leu | missense_variant | 7/18 | ENST00000358487.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000457416.7 | c.755C>T | p.Ser252Leu | missense_variant | 7/18 | 1 | NM_022970.4 | P4 | |
FGFR2 | ENST00000358487.10 | c.755C>T | p.Ser252Leu | missense_variant | 7/18 | 1 | NM_000141.5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000560 AC: 14AN: 249864Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135098
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1460734Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 726542
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Crouzon syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Apr 16, 2018 | This variant is interpreted as a Benign, for Crouzon syndrome, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:9002682). BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:9002682). - |
Likely benign, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 30, 2020 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2022 | Reported in individuals with Crouzon syndrome, inherited from apparently unaffected parents (Oldridge et al., 1997; Ohishi et al., 2017); Reported in a family where affected members had severe syndactyly without craniosynostosis and harbored a second FGFR2 variant in cis with p.(S252L) (Wilkie et al., 2002).; 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: 15282208, 15840724, 9700203, 26003532, 17621648, 9300656, 27683237, 32908727, 31348830, 9002682, 12357470, 29037998, 20301628) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | FGFR2: BS1 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2024 | Variant summary: FGFR2 c.755C>T (p.Ser252Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. c.755C>T has been reported in the literature in two independent families affected with Crouzon syndrome and the variant was present in both affected individuals as well as clinically normal family members (examples: Oldridge_1997, Oshini_2017). Additionally, this variant was seen in cis with a second pathogenic variant in a mother and her daughter affected with syndactyly (Wilkie_2002). At least one publication reports experimental evidence that FGFR2 mutant Ser252Leu exhibited kinetic behavior identical to wild-type (Anderson_1998). These data suggest a benign role for this variant however, other variants affecting this residue have been classified pathogenic/likely pathogenic in ClinVar (CV IDs: 13272, 13279). ClinVar contains an entry for this variant (Variation ID: 549484). The following publications have been ascertained in the context of this evaluation (PMID: 9002682, 9700203, 15282208, 11711827, 27683237, 12357470). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
FGFR2-related craniosynostosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2023 | This variant is also known as 934C>T. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 9002682, 11711827, 27683237). This variant is present in population databases (rs79184941, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 252 of the FGFR2 protein (p.Ser252Leu). ClinVar contains an entry for this variant (Variation ID: 549484). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser252 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719344, 8651276, 9462761, 11390973, 22664175, 23495007, 24489893, 25867380). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FGFR2 function (PMID: 9700203). 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. - |
FGFR2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2022 | The FGFR2 c.755C>T variant is predicted to result in the amino acid substitution p.Ser252Leu. This variant has been reported in several individuals with Crouzon syndrome, but it has also been observed in clinically normal members with the families (Oldridge et al 1997. PubMed ID: 9002682; Sakai N et al 2001. PubMed ID: 11711827; Ohishi et al. 2016. PbuMed ID: 27683237). In one study, functional analysis of this variant revealed wild-type kinetic (Anderson J et al 1998. PubMed ID: 9700203). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-123279677-G-A). A different substitution affecting the same amino acid (p.Ser252Trp) has been reported in association with Apert syndrome (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at