ClinVar Miner

Submissions for variant NM_023110.2(FGFR1):c.232C>T (p.Arg78Cys) (rs1554570706)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498444 SCV000589579 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing The R78C variant in the FGFR1 gene has been published previously in association with Kallmann syndrome; however, no detailed segregation information was provided (Pitteloud et al., 2006; Miraoui et al., 2013). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R78C 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 Arginine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000704507 SCV000833458 likely pathogenic Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome 2018-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 78 of the FGFR1 protein (p.Arg78Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with Kallmann syndrome (PMID: 16764984) and several individuals with hypogonadotropic hypogonadism (PMID: 16764984, 23643382, 28754744, Invitae). ClinVar contains an entry for this variant (Variation ID: 431966). Experimental studies in myoblast cells have shown that this missense change, p.Arg78Cys, exhibits a decrease in response to FGF21 compared to cells without this variant (PMID: 28754744). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genetics Department,Polish Mother's Memorial Hospital Research Institute RCV001004067 SCV000996495 likely pathogenic Hypogonadotropic hypogonadism 2 with or without anosmia 2019-08-27 criteria provided, single submitter research

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