ClinVar Miner

Submissions for variant NM_023110.3(FGFR1):c.1042G>A (p.Gly348Arg)

dbSNP: rs886037634
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000319353 SCV000329590 pathogenic not provided 2020-03-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23643382, 25394172, 20536592, 25497574, 29419413, 32724172)
Reproductive Endocrine Unit, Massachusetts General Hospital RCV001542473 SCV003932548 pathogenic Hypogonadotropic hypogonadism 2 with or without anosmia 2023-05-04 criteria provided, single submitter research The variant has been classified as P2 based on the variant meeting the following ACMG Criteria: PS2,PM2,PP3,PP1,PP2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004537181 SCV004122482 pathogenic FGFR1-related disorder 2023-10-31 criteria provided, single submitter clinical testing Variant summary: FGFR1 c.1042G>A (p.Gly348Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249898 control chromosomes. c.1042G>A has been reported in the literature in individuals affected with autosomal dominant congenital hypogonadotropic hypogonadism and Kallmann syndrome, including at-least two de novo occurences (example, Acierno_2020, Zhang_2021, BailleulForestier_2010). These data indicate that the variant is very likely associated with FGFR1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished response of fibroblast growth factor 8 stimulation (Acierno_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32724172, 34348883, 20536592). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000043588 SCV000071606 risk factor Hypogonadotropic hypogonadism 2 with anosmia 2015-08-01 no assertion criteria provided literature only
Genomics England Pilot Project, Genomics England RCV001542473 SCV001760212 pathogenic Hypogonadotropic hypogonadism 2 with or without anosmia no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004537181 SCV005366101 pathogenic FGFR1-related disorder 2024-08-30 no assertion criteria provided clinical testing The FGFR1 c.1042G>A variant is predicted to result in the amino acid substitution p.Gly348Arg. This variant has been reported in many individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Bailleul-Forestier et al. 2010. PubMed ID: 20536592; Table S3, Miraoui et al. 2013. PubMed ID: 23643382; Table S2, Cassatella et al. 2018. PubMed ID: 29419413; Acierno et al. 2020. PubMed ID: 32724172). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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