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

gnomAD frequency: 0.00001  dbSNP: rs80053154

Total submissions: 7

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