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NM_005249.5(FOXG1):c.256dup (p.Gln86fs) AND Rett syndrome, congenital variant

Germline classification:
Pathogenic (5 submissions)
Last evaluated:
Apr 17, 2023
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:
RCV000170074.13

Allele description

NM_005249.5(FOXG1):c.256dup (p.Gln86fs)

Gene:
FOXG1:forkhead box G1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
14q12
Genomic location:
Preferred name:
NM_005249.5(FOXG1):c.256dup (p.Gln86fs)
Other names:
NM_005249.5(FOXG1):c.256dup; p.Gln86fs
HGVS:
  • NC_000014.9:g.28767535dup
  • NG_009367.1:g.5455dup
  • NM_005249.5:c.256dupMANE SELECT
  • NP_005240.3:p.Gln86fs
  • NC_000014.8:g.29236734_29236735insC
  • NC_000014.8:g.29236741dup
  • NM_005249.3:c.256dup
  • NM_005249.3:c.256dupC
  • NM_005249.4:c.256dup
  • NM_005249.4:c.256dupC
  • NM_005249.5:c.256dupCMANE SELECT
  • p.Q86PfsX35
Protein change:
Q86fs
Links:
dbSNP: rs786205001
NCBI 1000 Genomes Browser:
rs786205001
Molecular consequence:
  • NM_005249.5:c.256dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
4

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
SCV000222384RettBASE
no assertion criteria provided
Pathogenic
(Feb 15, 2013)
de novocuration

PubMed (4)
[See all records that cite these PMIDs]

SCV001203682Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Apr 17, 2023)
germlineclinical testing

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

SCV002026222Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 20, 2018)
germlineclinical testing

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

SCV002575065Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicde novoclinical testing

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

SCV002820305Neuberg Centre For Genomic Medicine, NCGM
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes4not providednot provided4Noclinical testing, curation
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements.

Allou L, Lambert L, Amsallem D, Bieth E, Edery P, Destrée A, Rivier F, Amor D, Thompson E, Nicholl J, Harbord M, Nemos C, Saunier A, Moustaïne A, Vigouroux A, Jonveaux P, Philippe C.

Eur J Hum Genet. 2012 Dec;20(12):1216-23. doi: 10.1038/ejhg.2012.127. Epub 2012 Jun 27.

PubMed [citation]
PMID:
22739344
PMCID:
PMC3499785

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.

Ellaway CJ, Ho G, Bettella E, Knapman A, Collins F, Hackett A, McKenzie F, Darmanian A, Peters GB, Fagan K, Christodoulou J.

Eur J Hum Genet. 2013 May;21(5):522-7. doi: 10.1038/ejhg.2012.208. Epub 2012 Sep 12.

PubMed [citation]
PMID:
22968132
PMCID:
PMC3641384
See all PubMed Citations (7)

Details of each submission

From RettBASE, SCV000222384.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providedNocuration PubMed (4)
2not provided1not providedNocuration PubMed (4)
3not provided1not providedNocuration PubMed (4)
4not provided1not providedNocuration PubMed (4)

Description

"Rett syndrome - congenital"
"Rett syndrome - congenital"
"Rett syndrome - congenital"
"Rett syndrome - classical"
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyes1bloodnot provided1not providednot providednot provided
2de novoyes1bloodnot provided1not providednot providednot provided
3de novoyes1bloodnot provided1not providednot providednot provided
4de novoyes1bloodnot provided1not providednot providednot provided

From Invitae, SCV001203682.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Ser472Ilefs*15) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189613). This variant is also known as c.256_257dupC. This premature translational stop signal has been observed in individual(s) with congenital variant of Rett syndrome (PMID: 20734096). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln86Profs*35) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the FOXG1 protein.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002026222.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV002575065.1

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV002820305.1

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

Description

The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed variant has been reported to ClinVar as Pathogenic. The p.Q86Pfs*35 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This pathogenic mutation is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jun 17, 2024