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Severe microcephaly

Gene: RAD50

Amber List (moderate evidence)

RAD50 (RAD50 double strand break repair protein)
EnsemblGeneIds (GRCh38): ENSG00000113522
EnsemblGeneIds (GRCh37): ENSG00000113522
OMIM: 604040, Gene2Phenotype
RAD50 is in 4 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are now a total of 3 unrelated cases (PMIDs: 19409520; 32212377; 33378670) with a RAD50‐related syndrome including microcephaly. This therefore reaches the threshold for promotion of this gene to Green status at the next review (removed 'watchlist' tag and added 'Q2_21_rating' tag)
Created: 1 Apr 2021, 3:48 p.m. | Last Modified: 1 Apr 2021, 3:48 p.m.
Panel Version: 2.106
- PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects (including microcephaly), who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.
Created: 1 Apr 2021, 3:40 p.m. | Last Modified: 1 Apr 2021, 3:40 p.m.
Panel Version: 2.105
Comment on list classification: Relevant phenotype (two unrelated cases with severe congenital microcephaly) but additional cases required before inclusion of RAD50 on a diagnostic panel.

Rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Created: 21 Sep 2020, 3:42 p.m. | Last Modified: 21 Sep 2020, 3:42 p.m.
Panel Version: 2.22

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nijmegen breakage syndrome-like disorder, OMIM:613078

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Two individuals reported with bi-allelic variants in this gene showing dysmorphic facial features similar to NBS, short stature, microcephaly, and mild/moderate intellectual disability. Fibroblasts established from one of the individuals showed chromosomal instability and abnormal radioresistant DNA synthesis. The MRE11/RAD50/NBN (MRN) complex is involved in signaling processes inducing the repair of DNA double-strand breaks. Variants in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)‐like disorder, respectively, so this gene is a strong biological candidate for this phenotype.
Sources: Literature
Created: 8 Sep 2020, 10:52 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nijmegen breakage syndrome-like disorder, MIM# 613078

Publications

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Nijmegen breakage syndrome-like disorder, OMIM:613078
Tags
Q2_21_rating
OMIM
604040
Clinvar variants
Variants in RAD50
Penetrance
None
Publications
Panels with this gene

History Filter Activity

1 Apr 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, 613078 to Nijmegen breakage syndrome-like disorder, OMIM:613078

1 Apr 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: RAD50 were set to 1887849; 19409520; 32212377

1 Apr 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: rad50 has been classified as Amber List (Moderate Evidence).

1 Apr 2021, Gel status: 2

Removed Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist was removed from gene: RAD50. Tag Q2_21_rating tag was added to gene: RAD50.

21 Sep 2020, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist tag was added to gene: RAD50.

21 Sep 2020, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, MIM# 613078 to Nijmegen breakage syndrome-like disorder, 613078

21 Sep 2020, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: RAD50 were set to 19409520; 32212377

21 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: rad50 has been classified as Amber List (Moderate Evidence).

8 Sep 2020, Gel status: 0

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

Zornitza Stark (Australian Genomics)

gene: RAD50 was added gene: RAD50 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAD50 were set to 19409520; 32212377 Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078 Review for gene: RAD50 was set to GREEN gene: RAD50 was marked as current diagnostic