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Intellectual disability
Gene: PRKAR1B

PRKAR1B (protein kinase cAMP-dependent type I regulatory subunit beta)
EnsemblGeneIds (GRCh38): ENSG00000188191
EnsemblGeneIds (GRCh37): ENSG00000188191
OMIM: 176911, Gene2Phenotype
PRKAR1B is in 2 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.

Panel Version: 5.286

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Created: 11 Oct 2023, 9:34 a.m.
Last Modified: 11 Oct 2023, 9:34 a.m.
Panel version: 5.286

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Created: 3 May 2023, 5:45 p.m. | Last Modified: 3 May 2023, 5:45 p.m.

Panel Version: 5.98

Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Created: 3 May 2023, 5:44 p.m. | Last Modified: 3 May 2023, 5:44 p.m.

Panel Version: 5.98

Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Created: 3 May 2023, 5:44 p.m. | Last Modified: 3 May 2023, 5:44 p.m.

Panel Version: 5.97

As reviewed by Zornitza Stark (Australian Genomics) and Konstantinos Varvagiannis, there are six unrelated individuals carrying heterozygous missense PRKAR1B variants. Three variants are reported in total and four patients carried the same variant p.Arg335Trp. All six patients presented with global developmental delay, autism spectrum disorder and apraxia/dyspraxia.

This gene has been associated with relevant phenotypes in OMIM (MIM #619680) and Gene2Phenotype (with 'moderate' rating in the DD panel).
Created: 3 May 2023, 5:36 p.m. | Last Modified: 3 May 2023, 5:36 p.m.

Panel Version: 5.93

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680

Publications

33833410

Created: 3 May 2023, 5:36 p.m.
Last Modified: 3 May 2023, 5:36 p.m.
Panel version: 5.93

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Manuscript now published PMID 33833410:
6 individuals reported with neurodevelopmental disorders, 5 confirmed de novo. 4 carried the same variant p.(Arg335Trp).

Phenotypes include global developmental delay, autism spectrum disorder, apraxia/dyspraxia. 3 patients, all with the p.(Arg335Trp) variant, also had reduced pain sensitivity and congenital hypotonia.
Created: 3 Feb 2022, 9:48 p.m. | Last Modified: 3 Feb 2022, 9:48 p.m.

Panel Version: 3.1496

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Marbach-Schaaf neurodevelopmental syndrome MIM#619680

Publications

33833410

Created: 3 Feb 2022, 9:48 p.m.
Last Modified: 3 Feb 2022, 9:48 p.m.
Panel version: 3.1496

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the provided evidence this gene has been given an Amber rating.
Created: 12 Nov 2020, 3:14 p.m. | Last Modified: 12 Nov 2020, 3:14 p.m.

Panel Version: 3.525

Created: 12 Nov 2020, 3:14 p.m.
Last Modified: 12 Nov 2020, 3:14 p.m.
Panel version: 3.525

Konstantinos Varvagiannis (Other)

I don't know

Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Created: 1 Nov 2020, 3:17 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure

Publications

https://doi.org/10.1101/2020.09.10.20190314
25414040

Created: 1 Nov 2020, 3:17 p.m.

Panel version: 3.500

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
NHS GMS

Phenotypes

Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680

OMIM

176911

Clinvar variants

Variants in PRKAR1B

Penetrance

unknown

Publications

Panels with this gene

History Filter Activity

11 Oct 2023, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680

11 Oct 2023, Gel status: 3

Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist was removed from gene: PRKAR1B. Tag Q2_23_promote_green was removed from gene: PRKAR1B.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to PRKAR1B. Source Expert Review Green was added to PRKAR1B. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

3 May 2023, Gel status: 2