NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser) AND Rett syndrome, congenital variant

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(2);Uncertain significance(1) (Last evaluated: Mar 30, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000500932.3

Allele description [Variation Report for NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser)]

NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser)

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.670G>A (p.Gly224Ser)
HGVS:
  • NC_000014.9:g.28767949G>A
  • NG_009367.1:g.5869G>A
  • NM_005249.5:c.670G>AMANE SELECT
  • NP_005240.3:p.Gly224Ser
  • NP_005240.3:p.Gly224Ser
  • NC_000014.8:g.29237155G>A
  • NM_005249.3:c.670G>A
  • NM_005249.4:c.670G>A
Protein change:
G224S
Links:
dbSNP: rs727503935
NCBI 1000 Genomes Browser:
rs727503935
Molecular consequence:
  • NM_005249.5:c.670G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Rett syndrome, congenital variant
Identifiers:
MONDO: MONDO:0013270; MedGen: C3150705; Orphanet: 3095; OMIM: 613454

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000594858Genetic Services Laboratory, University of Chicagocriteria provided, single submitter
Likely pathogenic
(Mar 25, 2016)
germlineclinical testing

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

SCV000650056Invitaecriteria provided, single submitter
Uncertain significance
(Jan 24, 2017)
germlineclinical testing

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

SCV000700153Equipe Genetique des Anomalies du Developpement, Université de Bourgognecriteria provided, single submitter
Likely pathogenic
(Mar 30, 2017)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

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

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000594858.1

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

From Invitae, SCV000650056.1

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

Description

This sequence change replaces glycine with serine at codon 224 of the FOXG1 protein (p.Gly224Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FOXG1-related disease. ClinVar contains an entry for this variant (Variation ID: 167092). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000700153.1

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

Last Updated: Sep 18, 2021

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