Submissions for variant NM_004113.6(FGF12):c.155G>A (p.Arg52His)

dbSNP: rs886039903

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000258032	SCV000323204	pathogenic	Developmental and epileptic encephalopathy, 47	2016-09-15	criteria provided, single submitter	research
GeneDx	RCV000522341	SCV000618459	pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Published functional studies suggest the variant strongly changed the voltage dependence of inactivation gating, resulting in a gain-of-function effect and increased neuronal excitability (Siekierska et al., 2016); 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: 27830185, 28506426, 27872899, 28991257, 29652076, 33186347, 31164858, 34758253, 27164707, 28554332, 29100083, 28135719, 29699863, 30951195, 31780880, 33982289, 33349918, 33233562, 32645220, 32234142, 33287870, 31785789, 32368696)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000522341	SCV001447898	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000258032	SCV001520579	pathogenic	Developmental and epileptic encephalopathy, 47	2023-07-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000522341	SCV001582005	pathogenic	not provided	2024-11-18	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 114 of the FGF12 protein (p.Arg114His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 27164707, 27830185, 27872899, 28506426, 28554332). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg52His. ClinVar contains an entry for this variant (Variation ID: 266034). Invitae Evidence 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 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 FGF12 protein function. Experimental studies have shown that this missense change affects FGF12 function (PMID: 27164707). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000258032	SCV002011972	pathogenic	Developmental and epileptic encephalopathy, 47	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated individuals (PMID: 27164707, 29699863, and 29652076, PS2 and PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27164707, PS3). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000258032	SCV002526734	pathogenic	Developmental and epileptic encephalopathy, 47	2022-05-31	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS2_VSTR, PS4, PS3_MOD, PM1, PM2_SUP, PP3
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV002294210	SCV002586387	pathogenic	Seizure	2022-10-25	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000522341	SCV002818202	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000258032	SCV004036019	pathogenic	Developmental and epileptic encephalopathy, 47		criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000522341	SCV005197914	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV000522341	SCV005328404	pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing
OMIM	RCV000258032	SCV000328198	pathogenic	Developmental and epileptic encephalopathy, 47	2021-11-29	no assertion criteria provided	literature only
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000522341	SCV000778247	pathogenic	not provided	2017-03-15	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001249217	SCV001423151	not provided	Early onset epileptic encephalopathy		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 06-12-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genomics England Pilot Project, Genomics England	RCV000258032	SCV001760115	likely pathogenic	Developmental and epileptic encephalopathy, 47		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000522341	SCV001798098	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000522341	SCV001807065	pathogenic	not provided		no assertion criteria provided	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000258032	SCV001984526	pathogenic	Developmental and epileptic encephalopathy, 47	2020-11-01	flagged submission	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000258032	SCV002318930	pathogenic	Developmental and epileptic encephalopathy, 47		no assertion criteria provided	clinical testing