4-1801844-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000142.5(FGFR3):c.749C>T(p.Pro250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,606,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P250R) has been classified as Pathogenic.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000418 AC: 1AN: 238970Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131106
GnomAD4 exome AF: 0.00000619 AC: 9AN: 1454808Hom.: 0 Cov.: 39 AF XY: 0.00000692 AC XY: 5AN XY: 722916
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 250 of the FGFR3 protein (p.Pro250Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of FGFR3-related conditions (PMID: 12362036). ClinVar contains an entry for this variant (Variation ID: 533893). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FGFR3 protein function with a positive predictive value of 80%. This variant disrupts the p.Pro250 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9042914, 10094188, 10861678, 15915095, 26740388). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
FGFR3-related disorder Uncertain:1
The FGFR3 c.749C>T variant is predicted to result in the amino acid substitution p.Pro250Leu. This variant was reported in an individual with craniosynostosis and found to be inherited from her very mildly affected mother (Schindler et al 2002. PubMed ID: 12362036). This variant is reported in 0.0041% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-1803571-C-T). A different missense variant affecting the same amino acid is a common cause of isolated craniosynostosis (see for example, Kruszka. 2016. PubMed ID: 26740388 ). Although we suspect that this variant may be pathogenic, at this time, the clinical significance 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