ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1052C>G (p.Ser351Cys) (rs1057517964)

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Total submissions: 2
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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 RCV000811883 SCV000952173 pathogenic Craniosynostosis syndrome 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 351 of the FGFR3 protein (p.Ser351Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of autosomal dominant FRFR3-related conditions (PMID: 18328977, 18391498, 15793702, 25271085, 12357470, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372751). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. For these reasons, this variant has been classified as Pathogenic.

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