NM_005249.5(FOXG1):c.214C>T (p.Gln72Ter) AND Rett syndrome, congenital variant

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 20, 2018
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:: RCV000576162.8

Allele description [Variation Report for NM_005249.5(FOXG1):c.214C>T (p.Gln72Ter)]

NM_005249.5(FOXG1):c.214C>T (p.Gln72Ter)

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.214C>T (p.Gln72Ter)

HGVS:

NC_000014.9:g.28767493C>T
NG_009367.1:g.5413C>T
NM_005249.5:c.214C>TMANE SELECT
NP_005240.3:p.Gln72Ter
NC_000014.8:g.29236699C>T
NM_005249.4:c.214C>T

Protein change:

Q72*

Links:

dbSNP: rs1555321237

NCBI 1000 Genomes Browser:

rs1555321237

Molecular consequence:

NM_005249.5:c.214C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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MICAL3 microtubule associated monooxygenase, calponin and LIM domain containing ...
MICAL3 microtubule associated monooxygenase, calponin and LIM domain containing 3 [Homo sapiens]
Gene ID:57553

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000676978	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 26, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24836831, 28492532
SCV002026218	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2018)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28661489, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000676978

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 26, 2017)

germline

clinical testing

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

SCV002026218

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 20, 2018)

de novo

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	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

Epilepsy and outcome in FOXG1-related disorders.

Seltzer LE, Ma M, Ahmed S, Bertrand M, Dobyns WB, Wheless J, Paciorkowski AR.

Epilepsia. 2014 Aug;55(8):1292-300. doi: 10.1111/epi.12648. Epub 2014 May 16.

PubMed [citation]

PMID:: 24836831
PMCID:: PMC4265461

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000676978.4

#	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. Multiple truncations downstream of this variant have been determined to be pathogenic (PMID: 24836831). This suggests that deletion of this region of the FOXG1 protein is causative of disease. This variant has not been reported in the literature in individuals with a FOXG1-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Gln72*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 418 amino acids 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, SCV002026218.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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