Submissions for variant NM_000142.5(FGFR3):c.833A>G (p.Tyr278Cys)

dbSNP: rs121913115

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415056	SCV000492819	pathogenic	Short stature	2015-06-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513085	SCV003525583	pathogenic	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 278 of the FGFR3 protein (p.Tyr278Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypochondroplasia (PMID: 16912704, 24411048, 29595812). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16357). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002513085	SCV005870217	pathogenic	not provided	2024-08-23	criteria provided, single submitter	clinical testing	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: 24411048, 24229583, 26770560, 29595812, 16912704)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002513085	SCV005878622	likely pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	The FGFR3 c.833A>G; p.Tyr278Cys variant (rs121913115, ClinVar Variation ID: 16357) is reported in the literature in individuals affected with achondroplasia and hypochondroplasia (Chandler 2018, Chen 2013, Cheung 2024, Heuertz 2006, Zhao 2015). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.785). Based on available information, this variant is considered to be likely pathogenic. References: Chandler N et al. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genet Med. 2018 Nov;20(11):1430-1437. PMID: 29595812. Chen CP et al. Detection of a de novo Y278C mutation in FGFR3 in a pregnancy with severe fetal hypochondroplasia: prenatal diagnosis and literature review. Taiwan J Obstet Gynecol. 2013 Dec;52(4):580-5. PMID: 24411048. Cheung MS et al. Growth reference charts for children with hypochondroplasia. Am J Med Genet A. 2024 Feb;194(2):243-252. PMID: 37814549. Heuertz S et al. Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia. Eur J Hum Genet. 2006 Dec;14(12):1240-7. PMID: 16912704. Zhao R et al. Whole-exome sequencing and whole genome re-sequencing for prenatal diagnosis of achondroplasia. Int J Clin Exp Med. 2015 Oct 15;8(10):19241-9. PMID: 26770560.
OMIM	RCV000017768	SCV000038046	pathogenic	Hypochondroplasia	2006-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000017768	SCV000086725	not provided	Hypochondroplasia		no assertion provided	literature only	Phenotype resembles achondroplasia in newborns [Heuertz et al 2006, Song et al 2012].