Submissions for variant NM_000142.5(FGFR3):c.2421A>G (p.Ter807Trp)

dbSNP: rs121913103

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV000055766	SCV000992335	pathogenic	Thanatophoric dysplasia type 1	2019-04-05	criteria provided, single submitter	clinical testing	This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results in the elimination of a termination codon and subsequent protein elongation. The 141 amino acid residues resulting from the elimination for the termination codon contain a highly hydrophobic domain that is rich in cysteine, which is consistent with the known molecular mechanism for TD type I. We consider this variant pathogenic.
GeneDx	RCV001569868	SCV001794029	pathogenic	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Stop codon loss and change to a tryptophan codon, leading to protein extension and the addition of 101 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10425034, 25728633, 25614871, 19215249, 17509076, 17320202, 34358384)
Blueprint Genetics	RCV001569868	SCV001832258	pathogenic	not provided	2019-10-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001569868	SCV002507664	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	This protein extension has been observed in individuals with thanatophoric dysplasia type I (PMID: 10425034, 25614871). 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: 10425034, 25728633; Invitae). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 65564). This variant is also known as p.X807Trp. 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.
MGZ Medical Genetics Center	RCV000055766	SCV002579214	likely pathogenic	Thanatophoric dysplasia type 1	2022-04-19	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004760363	SCV005374306	likely pathogenic	Achondroplasia	2024-09-22	criteria provided, single submitter	clinical testing
GeneReviews	RCV000055766	SCV000086715	not provided	Thanatophoric dysplasia type 1		no assertion provided	literature only