Submissions for variant NM_000142.5(FGFR3):c.1052C>G (p.Ser351Cys)

dbSNP: rs1057517964

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413031	SCV000491208	likely pathogenic	not provided	2016-06-15	criteria provided, single submitter	clinical testing	The S351C variant in the FGFR3 gene has been reported previously in an individual with hypochondroplasia (Baujat et al., 2008). The S351C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S351C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret S351C as a likely pathogenic variant.
Invitae	RCV000413031	SCV000952173	pathogenic	not provided	2023-03-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser351 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30681580). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function. ClinVar contains an entry for this variant (Variation ID: 372751). This missense change has been observed in individual(s) with clinical features of autosomal dominant FRFR3-related conditions (PMID: 12357470, 15793702, 18328977, 18391498, 25271085; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 351 of the FGFR3 protein (p.Ser351Cys).