ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1950G>C (p.Lys650Asn) (rs28928868)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641204 SCV000762842 pathogenic Craniosynostosis syndrome 2017-09-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 650 of the FGFR3 protein (p.Lys650Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with  hypochondroplasia (PMID: 11055896). ClinVar contains an entry for this variant (Variation ID: 16347). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Two different missense substitutions at this codon (p.Lys650Thr and p.Lys650Gln) have been determined to be pathogenic (PMID: 18583390, 11055896, 16912704, 20453470). This suggests that the lysine residue is critical for FGFR3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV001269938 SCV001450306 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing
OMIM RCV000017756 SCV000038034 pathogenic Hypochondroplasia 2000-12-01 no assertion criteria provided literature only

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