ClinVar Miner

Submissions for variant NM_023110.3(FGFR1):c.817G>A (p.Val273Met)

dbSNP: rs1131691929
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492969 SCV000583162 likely pathogenic not provided 2015-09-01 criteria provided, single submitter clinical testing The V273M variant in the FGFR1 gene has been reported previously in two unrelated individuals with Kallman syndrome, one of whom also had cleft palate (Albuisson et al., 2005; Pitteloud et al., 2006). Computational structural analysis shows that the V273M variant decreases affinity towards its binding partner FGF and SH2 (Rajith et al., 2013). The V273M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V273M variant 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 across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The V273M variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV001851361 SCV002178538 pathogenic Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome 2022-04-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 430370). This missense change has been observed in individual(s) with autosomal dominant Kallmann syndrome (PMID: 15605412, 16764984; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 273 of the FGFR1 protein (p.Val273Met).
Reproductive Endocrine Unit, Massachusetts General Hospital RCV003234560 SCV003932535 uncertain significance Hypogonadotropic hypogonadism 2 with or without anosmia 2023-05-04 criteria provided, single submitter research The variant has been classified as VUS based on the variant meeting the following ACMG Criteria: PM2,PP3,PP1,PP4.

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