Submissions for variant NM_023110.3(FGFR1):c.231C>G (p.Asn77Lys)

gnomAD frequency: 0.00010  dbSNP: rs767195580

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237839	SCV001410621	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2023-07-31	criteria provided, single submitter	clinical testing	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: 963764). This missense change has been observed in individual(s) with Kallman syndrome (PMID: 18985070). This variant is present in population databases (rs767195580, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 77 of the FGFR1 protein (p.Asn77Lys).
GeneDx	RCV001547124	SCV001766756	uncertain significance	not provided	2024-06-03	criteria provided, single submitter	clinical testing	Identified in a patient with Kallman syndrome in published literature, however, this variant was also observed in two healthy controls in this study (PMID: 17154279); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23329143, 18985070, 18034870, 17154279, 34633109)
Fulgent Genetics, Fulgent Genetics	RCV002491770	SCV002792162	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Jackson-Weiss syndrome; Pfeiffer syndrome; Hartsfield-Bixler-Demyer syndrome; Osteoglophonic dysplasia; Trigonocephaly 1; Encephalocraniocutaneous lipomatosis	2022-01-07	criteria provided, single submitter	clinical testing
Reproductive Endocrine Unit, Massachusetts General Hospital	RCV003234572	SCV003932518	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia	2023-05-04	criteria provided, single submitter	research
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001547124	SCV005197919	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing