ClinVar Genomic variation as it relates to human health
NM_004113.6(FGF12):c.148G>A (p.Gly50Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004113.6(FGF12):c.148G>A (p.Gly50Ser)
Variation ID: 522854 Accession: VCV000522854.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q28 3: 192335441 (GRCh38) [ NCBI UCSC ] 3: 192053230 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 29, 2018 Oct 8, 2024 Feb 3, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004113.6:c.148G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004104.3:p.Gly50Ser missense NM_001377292.1:c.37G>A NP_001364221.1:p.Gly13Ser missense NM_001377293.1:c.76G>A NP_001364222.1:p.Gly26Ser missense NM_001377294.1:c.76G>A NP_001364223.1:p.Gly26Ser missense NM_021032.5:c.334G>A NP_066360.1:p.Gly112Ser missense NC_000003.12:g.192335441C>T NC_000003.11:g.192053230C>T NG_051966.1:g.397159G>A - Protein change
- G112S, G50S, G13S, G26S
- Other names
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- Canonical SPDI
- NC_000003.12:192335440:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| FGF12 | No evidence available | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
246 | 297 | |
Conditions - Germline
| Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 3, 2024 | RCV000626031.10 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV001860470.6 | |
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FGF12-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Oct 26, 2023 | RCV003892404.2 |
Submissions - Germline
| Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Mar 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 47
This p.G112S variant was also
(more...)
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746644.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Generalized tonic-clonic seizures (present) , Delayed speech and language development (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Mexican
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-03-26
Testing laboratory interpretation: Likely pathogenic
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Likely pathogenic
(Nov 29, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 47
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001164222.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Likely pathogenic
(Dec 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 47
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001573227.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Number of individuals with the variant: 1
Family history: yes
Sex: male
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Likely pathogenic
(Aug 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002568712.2
First in ClinVar: Sep 03, 2022 Last updated: Mar 04, 2023 |
Comment:
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); … (more)
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]) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 47
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048570.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Seizure (present) , Autism (present) , Global developmental delay (present)
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Pathogenic
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002262226.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Feb 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 47
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005049845.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Oct 26, 2023)
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no assertion criteria provided
Method: clinical testing
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FGF12-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004715542.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
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| Defining the phenotype of FHF1 developmental and epileptic encephalopathy. | Trivisano M | Epilepsia | 2020 | PMID: 32645220 |
| FGF12p.Gly112Ser variant as a cause of phenytoin/phenobarbital responsive epilepsy. | Paprocka J | Clinical genetics | 2019 | PMID: 31292943 |
| De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy. | Guella I | Neurology. Genetics | 2016 | PMID: 27872899 |
Text-mined citations for rs1553798675 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.