Submissions for variant NM_000142.5(FGFR3):c.2420G>C (p.Ter807Ser)

dbSNP: rs397515514

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001664800	SCV001474458	pathogenic	not provided	2020-04-23	criteria provided, single submitter	clinical testing	The FGFR3 c.2420G>C; p.Ter807SerextTer101 variant is reported in the literature in multiple individuals affected with thanatophoric dysplasia type I (TD1) or a related skeletal dysplasia (Gomes 2018, Liu 2019, Xue 2014). In at least one instance, the variant was not found in either parent of an affected individual, suggesting a de novo origin (Liu 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes loss of the canonical stop codon and extension of the protein by 101 amino acids. Other stop-loss variants in FGFR3 have been reported in individuals with TD1 or a related skeletal dysplasia and are considered disease-causing (Gomes 2018, Passos-Bueno 1999, Xue 2014). Based on available information, the p.Ter807SerextTer101 variant is considered to be pathogenic. References: Gomes MES et al. Novel and Recurrent Mutations in the FGFR3 Gene and Double Heterozygosity Cases in a Cohort of Brazilian Patients with Skeletal Dysplasia. Mol Syndromol. 2018 Feb;9(2):92-99. Liu Y et al. Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases. Diagn Pathol. 2019 Jul 13;14(1):76. Passos-Bueno MR et al. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat. 1999;14(2):115-25. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014 Nov;2(6):497-503.
GeneDx	RCV001664800	SCV001872646	pathogenic	not provided	2021-09-21	criteria provided, single submitter	clinical testing	Identified in unrelated patients with thanatophoric dysplasia in published literature (Chen et al., 2017; Gomes et al., 2018); Variant resulting in loss of the termination codon leading to protein extension by 101 amino acids; Several different variants resulting in similar protein extensions have been reported in the Human Gene Mutation Database associated with thanatophoric dysplasia (HGMD), and have apparently similar functional consequences on protein stability and/or processing (Bonaventure et al., 2007; Gibbs et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18923003, 17507011, 18328977, 25728633, 25614871, 30048571, 29593476, 31299979, 17509076, 17320202, 28254233)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276678	SCV002566630	pathogenic	Connective tissue disorder	2021-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV001664800	SCV003525585	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This variant is also known as c.2426G>C (p.X809S,101) or X807Ser or *807S. For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the FGFR3 protein. Other variant(s) that result in a similarly extended protein product (p.*807Leuext*101) have been determined to be pathogenic (PMID: 33942288). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 994395). This protein extension has been observed in individual(s) with achrondoplasia and/or thanatophoric dysplasia type I (PMID: 29593476, 31299979). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the FGFR3 mRNA. It is expected to extend the length of the FGFR3 protein by 101 additional amino acid residues.