Variant: NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser)

CA234034

167092 (ClinVar)

Gene: FOXG1

Condition: FOXG1 disorder

Inheritance Mode: Autosomal dominant inheritance

UUID: 19e564c0-0f26-42d4-8dcc-709b295fda70

Approved on: 2024-12-18

Published on: 2025-03-26

HGVS expressions

NM_005249.5:c.670G>A
NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser)
NC_000014.9:g.28767949G>A
CM000676.2:g.28767949G>A
NC_000014.8:g.29237155G>A
CM000676.1:g.29237155G>A
NC_000014.7:g.28306906G>A
NG_009367.1:g.5869G>A
ENST00000706482.1:c.670G>A
ENST00000313071.7:c.670G>A
ENST00000313071.6:c.670G>A
NM_005249.4:c.670G>A

Likely Pathogenic

• Met criteria codes: PP3 PM1 PM6 PS4_Moderate PM2_Supporting PS3_Supporting

• Not Met criteria codes: BA1 BS4 BS3 BS1 BS2 BP5 BP2 BP4 PS2 PS1 PP4 PP1 PM3 PM5

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Gly224Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID: 18571142, 28661489) (PM1). The p.Gly224Ser variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with gross motor delay and infantile spasms (Internal database - GeneDx) (PM6). Functional study has shown that this variant impacts protein function (PMID: 35163265) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Gly224Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting). The p.Gly224Ser variant has been observed in 3 individuals with neurodevelopmental disease (PMID: 30533527, Internal database - GeneDx, Internal database - University of Chicago) (PS4_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic based on ACMG/AMP criteria (PM1, PM6, PS3_supporting, PP3_supporting, PM2_supporting, PS4_moderate). (FOXG1 specification v3.0.0; approved on 12/18/2024)

Met criteria codes

• PP3: Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
• PM1: The p.Gly224Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID: 18571142, 28661489).
• PM6: The p.Gly224Ser variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with gross motor delay and infantile spasms (GeneDx internal database).
• PS4_Moderate: The p.Gly224Ser variant has been observed in 3 individuals with neurodevelopmental disease (PMID: 30533527, GeneDx internal database, University of Chicago internal database) (PS4_moderate).
• PM2_Supporting: The p.Gly224Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting).
• PS3_Supporting: Functional study has shown that this variant impacts protein function (PMID 35163265) (PS3_supporting).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: A missense variant in this codon, c.671G>A (p.Gly224Asp), was reported in ClinVar as Likely Pathogenic, as well as in PMID: 29655203 but there is insufficient evidence to classify as Pathogenic.