NM_005249.5(FOXG1):c.651C>G (p.Tyr217Ter) AND Rett syndrome, congenital variant

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 30, 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:: RCV001781547.5

Allele description [Variation Report for NM_005249.5(FOXG1):c.651C>G (p.Tyr217Ter)]

NM_005249.5(FOXG1):c.651C>G (p.Tyr217Ter)

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.651C>G (p.Tyr217Ter)

Other names:

p.Y217*:TAC>TAG; NM_005249.5(FOXG1):c.651C>G; p.Tyr217Ter

HGVS:

NC_000014.9:g.28767930C>G
NG_009367.1:g.5850C>G
NM_005249.5:c.651C>GMANE SELECT
NP_005240.3:p.Tyr217Ter
NC_000014.8:g.29237136C>G
NM_005249.3:c.651C>G

Protein change:

Y217*

Links:

dbSNP: rs796052464

NCBI 1000 Genomes Browser:

rs796052464

Molecular consequence:

NM_005249.5:c.651C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002026254	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
SCV003442282	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24836831, 26993267, 27001178, 30842224, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002026254

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]

SCV003442282

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2021)

germline

clinical testing

PubMed (5)
[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	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

FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.

Mitter D, Pringsheim M, Kaulisch M, Plümacher KS, Schröder S, Warthemann R, Abou Jamra R, Baethmann M, Bast T, Büttel HM, Cohen JS, Conover E, Courage C, Eger A, Fatemi A, Grebe TA, Hauser NS, Heinritz W, Helbig KL, Heruth M, Huhle D, Höft K, et al.

Genet Med. 2018 Jan;20(1):98-108. doi: 10.1038/gim.2017.75. Epub 2017 Jun 29.

PubMed [citation]

PMID:: 28661489

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

See all PubMed Citations (7)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002026254.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003442282.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 205487). This sequence change creates a premature translational stop signal (p.Tyr217*) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 273 amino acid(s) of the FOXG1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of FOXG1-related conditions (PMID: 24836831, 26993267, 27001178, 30842224).

#	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

Last Updated: Aug 16, 2025

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