Submissions for variant NM_004113.6(FGF12):c.148G>A (p.Gly50Ser)

dbSNP: rs1553798675

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000626031	SCV000746644	likely pathogenic	Developmental and epileptic encephalopathy, 47	2017-03-26	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000626031	SCV001164222	likely pathogenic	Developmental and epileptic encephalopathy, 47	2018-11-29	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000626031	SCV001573227	likely pathogenic	Developmental and epileptic encephalopathy, 47	2020-12-09	criteria provided, single submitter	clinical testing
Invitae	RCV001860470	SCV002262226	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 112 of the FGF12 protein (p.Gly112Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGF12-related conditions (PMID: 31292943, 32645220; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522854). 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) performed at Invitae indicates that this missense variant is not expected to disrupt FGF12 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001860470	SCV002568712	likely pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31292943, 32645220, 34020858, 27872899, Seiffert2021[article])
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000626031	SCV004048570	likely pathogenic	Developmental and epileptic encephalopathy, 47		criteria provided, single submitter	clinical testing	The FGF12 c.334G>A variant has been reported in heterozygous state in individuals affected with Developmental and epileptic encephalopathy 47 (Trivisano M et. al., 2020; Tian Q et al., 2021). The p.Gly112Ser variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid Gly at position 112 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Gly112Ser in FGF12 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003892404	SCV004715542	pathogenic	FGF12-related condition	2023-10-26	criteria provided, single submitter	clinical testing	The FGF12 c.334G>A variant is predicted to result in the amino acid substitution p.Gly112Ser. FGF12 is also referred to as FHF1 in the literature. This variant has been reported in three individuals with developmental and epileptic encephalopathy; in two subjects the variant was de novo and in one it was inherited (Paprocka et al. 2019. PubMed ID: 31292943; Trivisano et al. 2020. PubMed ID: 32645220; Seiffert et al. 2022. PubMed ID: 36029553). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. In vitro analysis suggested that p.Gly112Ser modified the biophysical kinetics of ion channel activity (Seiffert et al. 2022. PubMed ID: 36029553). This variant is interpreted as pathogenic.