ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1138G>C (p.Gly380Arg) (rs28931614)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727147 SCV000706143 pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Invitae RCV000641209 SCV000762848 pathogenic Craniosynostosis syndrome 2019-08-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 380 of the FGFR3 protein (p.Gly380Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This is the second most commonly observed variant in individuals affected with achondroplasia, accounting for ~20% of reported cases (PMID: 22045636, 25614871, 8723101, 22339077, 25691418). ClinVar contains an entry for this variant (Variation ID: 16328). A different variant (c.1138G>A) giving rise to the same protein effect observed here (p.Gly380Arg) has also been reported in individuals with achondroplasia and determined to be pathogenic (PMID: 25614871, 21739570, 25691418). Together, these two variants (c.1138G>A and c.1138G>C) are observed in ~90% of individuals with achondroplasia (PMID: 22045636, 25614871). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000987394 SCV001136682 pathogenic Hypochondroplasia 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV000727147 SCV001871012 pathogenic not provided 2021-08-26 criteria provided, single submitter clinical testing More than 99% of cases of achondroplasia are caused by this variant and another point mutation (c.1138 G>A) resulting in arginine-for-glycine substitutions in amino acid 380 of the gene (Foldynova-Trantirkova et al., 2012); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7913883, 29542187, 22045636, 33511985, 28679403, 8723101, 8078586, 29593476, 31566912, 33370388, 33368972, 30138938, 30160829, 28181399, 17683901, 22325359, 22339077, 21739570, 25614871, 28230213, 19088846, 23056398, 9857065, 25691418)
OMIM RCV000017725 SCV000038003 pathogenic Achondroplasia 1994-09-15 no assertion criteria provided literature only

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