ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.739G>A (p.Glu247Lys)

gnomAD frequency: 0.00001  dbSNP: rs565612580
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000415492 SCV000328406 uncertain significance Crouzon syndrome-acanthosis nigricans syndrome 2016-10-20 criteria provided, single submitter clinical testing
GeneDx RCV001764351 SCV002000989 uncertain significance not provided 2023-10-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001764351 SCV002507669 uncertain significance not provided 2022-03-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 247 of the FGFR3 protein (p.Glu247Lys). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 374825). This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.

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