ClinVar Miner

Submissions for variant NM_023110.3(FGFR1):c.1520G>A (p.Arg507His)

gnomAD frequency: 0.00009  dbSNP: rs369356672
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498726 SCV000590773 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing The R507H variant has not been published as a germline variant to our knowledge. It has been reported as a presumably somatic variant in an endometrial tumor and metastasis (Afrogheh et al., 2016). The variant is observed in 8/66740 (0.012%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). R507H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253587 SCV001429383 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia 2019-05-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001857029 SCV002219821 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome 2023-12-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 507 of the FGFR1 protein (p.Arg507His). This variant is present in population databases (rs369356672, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432990). 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. 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.
Fulgent Genetics, Fulgent Genetics RCV002481592 SCV002790554 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia; Jackson-Weiss syndrome; Pfeiffer syndrome; Hartsfield-Bixler-Demyer syndrome; Osteoglophonic dysplasia; Trigonocephaly 1; Encephalocraniocutaneous lipomatosis 2022-01-11 criteria provided, single submitter clinical testing

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