ClinVar Miner

Submissions for variant NM_023110.3(FGFR1):c.1922A>G (p.Asp641Gly)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wangler Lab, Baylor College of Medicine RCV002294741 SCV002587795 pathogenic Hartsfield-Bixler-Demyer syndrome criteria provided, single submitter clinical testing This missense FGFR1 variant at c.1922A>G (p.D641G) was seen on exome through the Texome project (R01HG011795) as a de novo variant in the patient (PS2). This variant is found in the tyrosine kinase domain of FGFR1, where heterozygous variants associated with Hartsfield syndrome cluster (PMID: 23812909, 26931467) (PM1).An allelic variant (p.D641N) has been previously identified de novo in an individual with FGFR1-related Hartsfield syndrome (PS1). This variant was found to be functionally defective and consistent with the dominant negative mechanism proposed for variants associated with Hartsfield syndrome (PMID: 26931467) (PS3). It has not been observed in gnomAD (PM2).This missense variant is predicted to be deleterious (CADD: 31.000) (PP3), and there is high conservation of this residue. We classify this variant as pathogenic.
Baylor Genetics RCV002294741 SCV003835626 pathogenic Hartsfield-Bixler-Demyer syndrome 2022-09-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003101705 SCV003199337 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome 2022-05-14 flagged submission clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 641 of the FGFR1 protein (p.Asp641Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. 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) performed at Invitae indicates that this missense variant is expected to disrupt FGFR1 protein function. 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.

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