ClinVar Miner

Submissions for variant NM_023110.2(FGFR1):c.1343G>A (p.Arg448Gln) (rs758138124)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540340 SCV000644846 uncertain significance Kallmann syndrome 2; Pfeiffer syndrome 2017-06-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 448 of the FGFR1 protein (p.Arg448Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs758138124, ExAC 0.02%). This variant has not been reported in the literature in individuals with an FGFR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. In summary, this variant has uncertain impact on FGFR1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757294 SCV000885454 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing The FGFR1 c.1343G>A; p.Arg448Gln variant (rs758138124) has been identified in a patient diagnosed with idiopathic hypogonadotropic hypogonadism, and functional studies showed that this variant reduced but did not entirely abolish the protein’s ability to bind to the transcription factor EMX1 (Kim 2010). Another variant affecting this amino acid, p.Arg448Trp, has been reported as pathogenic for GnRH deficiency (Show 2011). The p.Arg448Gln variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.02% (identified on 6 out of 30,782chromosomes). The arginine at position 448 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg448Gln variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Although the available evidence is suggestive of pathogenicity, the clinical significance of the p.Arg448Gln variant cannot be determined with certainty.

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