Submissions for variant NM_000142.5(FGFR3):c.2005C>G (p.Arg669Gly)

dbSNP: rs1490564667

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001567755	SCV000832202	uncertain significance	not provided	2024-11-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 669 of the FGFR3 protein (p.Arg669Gly). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with hypochondroplasia (PMID: 15863034). ClinVar contains an entry for this variant (Variation ID: 579912). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 26992226). 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.
GeneDx	RCV001567755	SCV001791499	uncertain significance	not provided	2025-02-04	criteria provided, single submitter	clinical testing	Observed in patients with hypochondroplasia in published literature; detailed clinical information and segregation analysis was not provided for one of the individuals (PMID: 15863034, 37806643); Reported to increase autophosphorylation in a study of activating cancer variants; no patient with skeletal dysplasia reported (PMID: 26992226); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28755412, 30545934, 38411226, 30355600, 26992226, 15863034, 37806643)
Blueprint Genetics	RCV001567755	SCV001832401	uncertain significance	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796287	SCV005418851	uncertain significance	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Colorectal cancer; Germ cell tumor of testis; LADD syndrome 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PS4_Supporting+PS3_Supporting
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001567755	SCV002036876	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001567755	SCV002037451	uncertain significance	not provided		no assertion criteria provided	clinical testing