Submissions for variant NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)

dbSNP: rs121909627

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644520	SCV000766219	pathogenic	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2023-03-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the FGFR1 protein (p.Pro252Arg). This variant is present in population databases (rs121909627, gnomAD 0.0009%). This missense change has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16279). 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. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 10942429, 14613973).
CeGaT Center for Human Genetics Tuebingen	RCV001200303	SCV001371225	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000017669	SCV002012499	pathogenic	Pfeiffer syndrome	2021-08-27	criteria provided, single submitter	research	ACMG codes: PS3; PS4; PM2; PP1; PP3; PP5
GeneDx	RCV001200303	SCV002319172	pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with a significantly increased bindings affinity for endogenous ligands; additionally functional studies in an animal model demonstrate a damaging effect potentially via aberrant activation of downstream target Cbfa1 (Ibrahimi et al., 2004; Zhou et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); 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, 27065010, 7795583, 24127277, 10861678, 14564217, 7874169, 16957473, 24497711, 10942429, 31837199, 31016899, 32510873, 31167513, 32139749, 30207415, 34159400, 31785789, 14613973, 25251565)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017670	SCV002768161	pathogenic	Jackson-Weiss syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 [HH2] (MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with FGFR1 -related conditions. It has mainly been reported in individuals with Pfeiffer syndrome (MIM#101600) but has been observed in one individual with Jackson-Weiss syndrome (MIM#123150) (ClinVar, LOVD, DECIPHER, PMIDs: 24127277, 31837199, 1456217, 10861678). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002496391	SCV002812328	pathogenic	Hypogonadotropic hypogonadism 2 with or without anosmia; Jackson-Weiss syndrome; Pfeiffer syndrome; Hartsfield-Bixler-Demyer syndrome; Osteoglophonic dysplasia; Trigonocephaly 1; Encephalocraniocutaneous lipomatosis	2021-07-17	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000017669	SCV004030499	pathogenic	Pfeiffer syndrome		criteria provided, single submitter	clinical testing
OMIM	RCV000017669	SCV000037946	pathogenic	Pfeiffer syndrome	2004-01-01	no assertion criteria provided	literature only
OMIM	RCV000017670	SCV000037947	pathogenic	Jackson-Weiss syndrome	2004-01-01	no assertion criteria provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000017669	SCV002011764	pathogenic	Pfeiffer syndrome	2021-06-17	no assertion criteria provided	clinical testing