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Fetal anomalies

Gene: AMBRA1

Red List (low evidence)
AMBRA1 (autophagy and beclin 1 regulator 1)
EnsemblGeneIds (GRCh38): ENSG00000110497
EnsemblGeneIds (GRCh37): ENSG00000110497
OMIM: 611359, Gene2Phenotype
AMBRA1 is in 1 panel

4 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

This gene and phenotype were reviewed during meetings between November 2023 & July 2024. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler, Alison Male and Lyn Chitty (North Thames GLH), Stephanie Allen, Natalie Bibb, Esther Kinning and Denise Williams (Central & South GLH) and Natalie Canham, Anna De Burca and Samantha Doyle R21 Clinical Oversight Group.
Created: 29 Aug 2024, 8:33 p.m. | Last Modified: 29 Aug 2024, 8:33 p.m.
Panel Version: 4.36
Created: 29 Aug 2024, 8:33 p.m.
Last Modified: 29 Aug 2024, 8:33 p.m.
Panel version: 4.36

Stephanie Allen (Birmingham Women's NHS Foundation Trust)

Red List (low evidence)

Not in any other panels; PMID:32333458 - five rare missense mutations of AMBRA1 in 352 NTDs cases, which were absent in 224 matched controls and LOF zebrafish; PMID:17589504 - Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects. No further publications, no definite gene disease association - might this be partially penetrant / and association. Suggest red / amber - currently amber, no further update on notes in PanelApp. Red.
Created: 29 Aug 2024, 8:07 p.m. | Last Modified: 29 Aug 2024, 8:07 p.m.
Panel Version: 4.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neural tube defects

Publications

Created: 29 Aug 2024, 8:07 p.m.
Last Modified: 29 Aug 2024, 8:07 p.m.
Panel version: 4.35

Arina Puzriakova (Genomics England Curator)

I don't know

Comment on list classification: New gene added by Zornitza Stark. Sufficient unrelated cases and supportive functional data. However, only a single publication linking this gene to human disease at present (PMID:32333458). Segregation data was not provided and penetrance remains unclear. AMBRA1 was investigated by targeted sequencing and so there also is a possibility of variants in other genes.

Currently the evidence is insufficient for a Green rating, but this may be revised if further cases/clinical evidence arise (added 'watchlist' tag)
Created: 26 Jan 2021, 3:34 p.m. | Last Modified: 26 Jan 2021, 3:34 p.m.
Panel Version: 1.183
- PMID: 32333458 (2020) - 5 missense variants were identified in 6 Han Chinese patients with neural tube defects including parietal/occipital encephalocele and/or spina bifida. In vitro and in vivo (zebrafish) assays showed that 4 variants affected autophagy initiation to various degrees. The fifth variant had no effect on autophagosome formation and was able to rescue the ambra1a‐MO knockdown phenotype in zebrafish as same as WT mRNA.

However, the variants were detected by targeted sequencing and no segregation data was available for any of the cases. 3 variants were also found at low frequencies (MAF: 8e‐6 to 5.785e‐5) in control databases, ExAC or gnomAD. There are no further reports linking AMBRA1 to human disease.

- PMID: 17589504 (2007) - Ambra1 null mice displayed severe neural tube defects and embryonic lethality associated with autophagy impairment
Created: 26 Jan 2021, 3:18 p.m. | Last Modified: 26 Jan 2021, 3:18 p.m.
Panel Version: 1.182

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neural tube defects

Publications

Created: 26 Jan 2021, 3:18 p.m.
Last Modified: 26 Jan 2021, 3:18 p.m.
Panel version: 1.182

Zornitza Stark (Australian Genomics)

Green List (high evidence)

5 rare missense variants were identified in 6 cases from a neural tube defect cohort, and 4 (p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) of them were functionally validated to affect autophagy regulation in vitro or zebrafish embryo development in vivo. There is also null mouse model with neural tube defects.
Sources: Literature
Created: 3 Aug 2020, 11:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neural tube defects

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 3 Aug 2020, 11:07 a.m.

Panel version: 1.74

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • NHS GMS
Phenotypes
  • Neural tube defects
Tags
watchlist
OMIM
611359
Clinvar variants
Variants in AMBRA1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

29 Aug 2024, Gel status: 1

Added New Source, Added New Source, Set publications, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source NHS GMS was added to AMBRA1. Source Expert Review Red was added to AMBRA1. Publications for gene: AMBRA1 were updated from 17589504; 32333458 to 32333458; 17589504 Rating Changed from Amber List (moderate evidence) to Red List (low evidence)

26 Jan 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: ambra1 has been classified as Amber List (Moderate Evidence).

26 Jan 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist tag was added to gene: AMBRA1.

3 Aug 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: AMBRA1 was added gene: AMBRA1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: AMBRA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AMBRA1 were set to 17589504; 32333458 Phenotypes for gene: AMBRA1 were set to Neural tube defects Review for gene: AMBRA1 was set to GREEN gene: AMBRA1 was marked as current diagnostic