ClinVar Miner

Submissions for variant NM_023110.3(FGFR1):c.1774G>A (p.Glu592Lys)

gnomAD frequency: 0.00001  dbSNP: rs755002934
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001875393 SCV002151630 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome 2023-07-07 criteria provided, single submitter clinical testing This variant is present in population databases (rs755002934, gnomAD 0.02%). 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. 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 FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1386784). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 592 of the FGFR1 protein (p.Glu592Lys).
Clinical Genomics Laboratory, Washington University in St. Louis RCV003452061 SCV004177009 uncertain significance Pfeiffer syndrome 2023-09-08 criteria provided, single submitter clinical testing The FGFR1 c.1774G>A (p.Glu592Lys) variant was identified at near heterozygous allelic fraction. This variant, to our knowledge, has not been reported in the medical literature and it is only observed on 1/152194 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant has been reported in the ClinVar database as a germline variant of uncertain significance in Pfeiffer syndrome by one submitter (ClinVar Variation ID: 1386784). Computational predictors are uncertain as to the impact of this variant on FGFR1 function. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) the FGFR1 c.1774G>A (p.Glu592Lys) variant is classified as a variant of uncertain significance (VUS).

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