ClinVar Miner

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

dbSNP: rs28928868
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001269938 SCV000762842 pathogenic not provided 2023-08-10 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 650 of the FGFR3 protein (p.Lys650Asn). This variant is present in population databases (rs28928868, gnomAD 0.007%). This missense change has been observed in individuals with hypochondroplasia (PMID: 11055896). ClinVar contains an entry for this variant (Variation ID: 16347). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. This variant disrupts the p.Lys650 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11055896, 16912704, 18583390, 20453470). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269938 SCV001450306 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000017756 SCV002059335 likely pathogenic Hypochondroplasia 2021-06-01 criteria provided, single submitter clinical testing
GeneDx RCV001269938 SCV002496221 pathogenic not provided 2022-03-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as K650N significantly increased constitutive kinase activation in the mutant protein but to a lesser degree than those K650 variants associated with more severe phenotypes (Bellus et al. 2000).; Observed in multiple unrelated families with hypochondroplasia whose clinical features, including radiographic findings and short stature, are on the milder end of the FGFR3 spectrum (Bellus et al., 2000).; This variant is associated with the following publications: (PMID: 17103447, 17561467, 19855393, 15863034, 20453470, 16912704, 17320202, 26152202, 17509076, 19066716, 26686047, 33726816, 11055896)
Fulgent Genetics, Fulgent Genetics RCV002496393 SCV002810473 pathogenic Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Levy-Hollister 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 2021-08-21 criteria provided, single submitter clinical testing
OMIM RCV000017756 SCV000038034 pathogenic Hypochondroplasia 2000-12-01 no assertion criteria provided literature only

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