Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV001089549 | SCV001244759 | likely pathogenic | Ectrodactyly | 2018-05-31 | criteria provided, single submitter | clinical testing | A homozygous missense variant, NM_000141.4(FGFR2):c.764G>A, has been identified in exon 7 of 18 of the FGFR2 gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 255 of the protein (NP_000132.3(FGFR2):p.(Arg255Gln)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the linker region between the D2 and D3 functional domains. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic and segregated with ectrodactyly and acinar dysplasia in this patient's family (Barnett CP, et al., (2016)). Additionally, functional analysis of transiently transfected HEK293 cells demonstrated that mutant FGFR2 (p.(Arg255Gln)) had similar basal phosphorylation levels as wild-type FGFR2. However, phosphorylation of mutant FGFR2 was not increased to the same level as wild-type FGFR2 following FGF2 stimulation, demonstrating a partial loss of function (Barnett CP, et al., (2016)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. |