ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1612A>G (p.Ile538Val)

gnomAD frequency: 0.00001  dbSNP: rs80053154
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269544 SCV001449602 pathogenic not provided 2015-02-24 criteria provided, single submitter clinical testing
Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University RCV000017754 SCV002032064 pathogenic Hypochondroplasia criteria provided, single submitter clinical testing The heterozygous missense variant, c.1612A>G (p.Ile538Val) in FGFR3 (rs80053154) was identified in a patient diagnosed with hypochondroplasia (HCH) and hypophosphatasia (HPP). This mutation has been previously reported in a Swedish family with typical HCH (Grigelioniene et al., 1998). Her mother who had short stature and disproportionately short arms and legs also harbored this mutation. She was also identified with the compound heterozygous variants, c.1460C>T (p.Ala487Val) and c.1479C>A (p.Asn493Lys), in ALPL gene (Porntaveetus et al., 2017).
Invitae RCV001269544 SCV002507705 pathogenic not provided 2023-01-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 26992226). 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. ClinVar contains an entry for this variant (Variation ID: 16345). This missense change has been observed in individuals with clinical features of FGFR3-related conditions and/or clinical features of hypochondroplasia (PMID: 10215410, 28763161, 30753492; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80053154, gnomAD 0.005%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 538 of the FGFR3 protein (p.Ile538Val).
GeneDx RCV001269544 SCV002578807 uncertain significance not provided 2023-05-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10215410, 34006472, 34662886, 29758562, 29739731, 30753492, 35627109, 28763161)
MGZ Medical Genetics Center RCV000017754 SCV002581421 likely pathogenic Hypochondroplasia 2022-02-24 criteria provided, single submitter clinical testing
OMIM RCV000017754 SCV000038032 pathogenic Hypochondroplasia 1998-01-01 no assertion criteria provided literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000017754 SCV001482388 likely pathogenic Hypochondroplasia 2019-05-31 no assertion criteria provided research

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