Submissions for variant NM_023110.3(FGFR1):c.2107G>A (p.Gly703Ser)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002834533	SCV003215188	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 703 of the FGFR1 protein (p.Gly703Ser). This variant is present in population databases (rs768957161, gnomAD 0.007%). This missense change has been observed in individual(s) with Kallmann syndrome (PMID: 16764984). ClinVar contains an entry for this variant (Variation ID: 2013252). 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. This variant disrupts the p.Gly703 amino acid residue in FGFR1. Other variant(s) that disrupt this residue have been observed in individuals with FGFR1-related conditions (PMID: 16764984, 23643382), which suggests that this may be a clinically significant amino acid residue. 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.
Reproductive Endocrine Unit, Massachusetts General Hospital	RCV003234594	SCV003932586	likely pathogenic	Hypogonadotropic hypogonadism 2 with or without anosmia	2023-05-04	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004545401	SCV004763378	uncertain significance	FGFR1-related disorder	2024-01-19	criteria provided, single submitter	clinical testing	The FGFR1 c.2107G>A variant is predicted to result in the amino acid substitution p.Gly703Ser. This variant has been reported in an individual with Kallmann syndrome (Table 1, Pitteloud et al. 2006. PubMed ID: 16764984). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Gly703Arg) has also been reported in individual with Kallmann syndrome (Table 1, Pitteloud et al. 2006. PubMed ID: 16764984). Although we suspect this variant may be pathogenic, at this time, the clinical significance of the variant is uncertain due to the absence of conclusive functional and genetic evidence.