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NM_005249.5(FOXG1):c.458G>T (p.Gly153Val) AND Rett syndrome, congenital variant

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jun 28, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000585847.9

Allele description [Variation Report for NM_005249.5(FOXG1):c.458G>T (p.Gly153Val)]

NM_005249.5(FOXG1):c.458G>T (p.Gly153Val)

Gene:
FOXG1:forkhead box G1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q12
Genomic location:
Preferred name:
NM_005249.5(FOXG1):c.458G>T (p.Gly153Val)
HGVS:
  • NC_000014.9:g.28767737G>T
  • NG_009367.1:g.5657G>T
  • NM_005249.5:c.458G>TMANE SELECT
  • NP_005240.3:p.Gly153Val
  • NC_000014.8:g.29236943G>T
  • NM_005249.4:c.458G>T
Protein change:
G153V
Links:
dbSNP: rs1555321286
NCBI 1000 Genomes Browser:
rs1555321286
Molecular consequence:
  • NM_005249.5:c.458G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Rett syndrome, congenital variant
Identifiers:
MedGen: C3150705; Orphanet: 3095; OMIM: 613454

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000693809NeuroMeGen, Hospital Clinico Santiago de Compostela
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 1, 2018) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001216410Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jun 28, 2021) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot provided1not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients.

Fernández-Marmiesse A, Roca I, Díaz-Flores F, Cantarín V, Pérez-Poyato MS, Fontalba A, Laranjeira F, Quintans S, Moldovan O, Felgueroso B, Rodríguez-Pedreira M, Simón R, Camacho A, Quijada P, Ibanez-Mico S, Domingno MR, Benito C, Calvo R, Pérez-Cejas A, Carrasco ML, Ramos F, Couce ML, et al.

Front Neurosci. 2019;13:1135. doi: 10.3389/fnins.2019.01135.

PubMed [citation]
PMID:
31780880
PMCID:
PMC6856296
See all PubMed Citations (3)

Details of each submission

From NeuroMeGen, Hospital Clinico Santiago de Compostela, SCV000693809.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyes1not providednot provided1not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001216410.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 495264). This variant has been observed in individual(s) with epilepsy and dyskenesia (PMID: 31780880). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces glycine with valine at codon 153 of the FOXG1 protein (p.Gly153Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 25, 2025