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 [Variation Report for NM_005249.5(FOXG1):c.256dup (p.Gln86fs)]

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:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222384	RettBASE	no assertion criteria provided	Pathogenic (Feb 15, 2013)	de novo	curation	PubMed (4) [See all records that cite these PMIDs] 22739344, 22968132, 20734096, 22129046
SCV001203682	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20734096, 28492532
SCV002026222	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28661489, 25741868
SCV002575065	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002820305	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	4	not provided	not provided	4	No	clinical testing, curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	No	curation	PubMed (4)
2	not provided	1	not provided	No	curation	PubMed (4)
3	not provided	1	not provided	No	curation	PubMed (4)
4	not provided	1	not provided	No	curation	PubMed (4)

Description

"Rett syndrome - congenital"

PubMed [ID: 22739344]

"Rett syndrome - congenital"

PubMed [ID: 22968132]

"Rett syndrome - congenital"

PubMed [ID: 20734096]

"Rett syndrome - classical"

PubMed [ID: 22129046]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
2	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
3	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
4	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided

From Invitae, SCV001203682.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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