Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001851846 | SCV002246688 | pathogenic | FGFR2-related craniosynostosis | 2023-03-17 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala344 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8644708, 11556600, 22665975). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 13269). This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 7874170). 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 alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 344 of the FGFR2 protein (p.Ala344Gly). |
| 3billion | RCV003313919 | SCV004013786 | pathogenic | Pfeiffer syndrome | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75; 3Cnet: 0.40). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000013269 / PMID: 7874170) and a different missense change at the same codon (p.Ala344Pro / ClinVar ID: VCV001076383 / PMID: 8644708) have been previously reported to be associated with FGFR2 related disorder. The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 7581378, 7874170). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. | |
| OMIM | RCV000014187 | SCV000034435 | pathogenic | Jackson-Weiss syndrome | 1995-08-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000014188 | SCV000034436 | pathogenic | Crouzon syndrome | 1995-08-01 | no assertion criteria provided | literature only |