NM_005249.5(FOXG1):c.694A>G (p.Asn232Asp) AND Rett syndrome, congenital variant

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 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:: RCV000648315.9

Allele description [Variation Report for NM_005249.5(FOXG1):c.694A>G (p.Asn232Asp)]

NM_005249.5(FOXG1):c.694A>G (p.Asn232Asp)

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.694A>G (p.Asn232Asp)

HGVS:

NC_000014.9:g.28767973A>G
NG_009367.1:g.5893A>G
NM_005249.5:c.694A>GMANE SELECT
NP_005240.3:p.Asn232Asp
NC_000014.8:g.29237179A>G
NM_005249.4:c.694A>G

Protein change:

N232D

Links:

dbSNP: rs786205486

NCBI 1000 Genomes Browser:

rs786205486

Molecular consequence:

NM_005249.5:c.694A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000770129	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 31, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086512	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26993267, 27029630, 28851325, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000770129

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 31, 2017)

germline

clinical testing

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

SCV005086512

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (4)
[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

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

Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.

Trump N, McTague A, Brittain H, Papandreou A, Meyer E, Ngoh A, Palmer R, Morrogh D, Boustred C, Hurst JA, Jenkins L, Kurian MA, Scott RH.

J Med Genet. 2016 May;53(5):310-7. doi: 10.1136/jmedgenet-2015-103263. Epub 2016 Mar 18.

PubMed [citation]

PMID:: 26993267
PMCID:: PMC4862068

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000770129.5

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed to be de novo in an individual affected with FOXG1-related disease (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 232 of the FOXG1 protein (p.Asn232Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086512.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome, congenital variant (MIM#613454). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Three alternative amino acid changes at the same position have been classified as pathogenic in ClinVar and/or observed in individals with Rett-like conditions/movement disorders (PMIDs: 28851325, 27029630, 26993267). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic in ClinVar by a clinical laboratory who observed it as de novo in an individual with a FOXG1-related condition. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Duo analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Feb 25, 2025

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