Submissions for variant NM_023110.3(FGFR1):c.1399G>A (p.Glu467Lys)

gnomAD frequency: 0.00001  dbSNP: rs923019674

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV005040210	SCV005680226	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Jackson-Weiss syndrome; Pfeiffer syndrome; Hartsfield-Bixler-Demyer syndrome; Osteoglophonic dysplasia; Trigonocephaly 1; Encephalocraniocutaneous lipomatosis	2024-02-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357941	SCV001553552	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FGFR1 p.Glu463Lys variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs923019674) and in control databases in 4 of 280958 chromosomes at a frequency of 0.00001424 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 2 of 24196 chromosomes (freq: 0.000083), Latino in 1 of 35376 chromosomes (freq: 0.000028) and European (non-Finnish) in 1 of 128714 chromosomes (freq: 0.000008), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Glu463 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV003151307	SCV003839538	uncertain significance	not specified	2022-05-09	no assertion criteria provided	clinical testing	DNA sequence analysis of the FGFR1 gene demonstrated a sequence change, c.1399G>A, in exon 10 that results in an amino acid change, p.Glu467Lys. This sequence change has previously been described in two unrelated families with non-syndromic cleft lip and palate, but did not segregate with all affected family members (PMID: 17360555). This sequence change has been described in the gnomAD database with a frequency of 0.008% in the African/African American subpopulation (dbSNP rs923019674). The p.Glu467Lys change affects a moderately conserved amino acid residue located in a domain of the FGFR1 protein that is known to be functional. The p.Glu467Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu467Lys change remains unknown at this time. Heterozygous mutations in FGFR1 are associated with hypogonadotropic hypogonadism type 2 [OMIM#147950], Hartsfield syndrome [OMIM#615465], Jackson-Weiss syndrome [OMIM#123150], osteoglophonic dysplasia [OMIM#166250], Pfeiffer syndrome [OMIM#101600], and trigonocephaly type 1 [OMIM#190440].