chr17-68530405-C-T

Position:

• chr17-68530405-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002734.5(PRKAR1A):​c.1102C>T​(p.Arg368*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAR1A NM_002734.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 2.40

Genes affected

PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

PRKAR1A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-68530405-C-T is Pathogenic according to our data. Variant chr17-68530405-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68530405-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-68530405-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.1102C>T	p.Arg368*	stop_gained	11/11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.1102C>T	p.Arg368*	stop_gained	11/11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrodysostosis 1 with or without hormone resistance Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 06, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 23, 2021	The PRKAR1A c.1102C>T (p.Arg368Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg368Ter variant has been identified in at least nine individuals (Linglart et al. 2011; Linglart et al. 2012), all of which were de novo. The p.Arg368Ter variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. This variant is located in the last exon and was shown to escape nonsense-mediated decay (Linglart et al. 2011). Functional studies measuring the phosphorylation of cAMP responsive element-binding (CREB) protein, in forskolin-stimulated lymphocytic cell lines, showed that CREB phosphorylation was significantly reduced in cells from patients when compared with cells from controls (Linglart et al. 2011). In addition, a knock-in mouse model expressing Arg368Ter showed growth retardation, peripheral acrodysostosis and facial dysostosis (Le Stunff et al. 2017). Based on the collective evidence and application of the ACMG criteria, the p.Arg368Ter variant is classified as pathogenic for acrodysostosis type 1. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26405036, 27589370). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 23043190, 28804209). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000029907 / PMID: 21651393). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID: 21651393; 26405036). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 11 of 11). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0600 - Variant is located in the cAMP-binding domain B (PMID: 21651393). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals with acrodysostosis(PMID: 21651393; 23043190; 22464250). (P) 1002 - Moderate functional evidence supporting abnormal protein function (PMID: 26405036; 21651393). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -

not provided Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2023	Published functional studies demonstrate a damaging effect: gain of function variant leading to impaired ability of cAMP to dissociate subunits of PKA and repression of PKA activity (Linglert et al. 2011; Rhayem et al. 2015); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 14 amino acids are lost; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34529350, 23043190, 28804209, 26405036, 21651393, 22464250, 29499646, 32782451, 34006472, 31785789) -

Carney complex, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects PRKAR1A function (PMID: 21651393, 26405036). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 29907). This premature translational stop signal has been observed in individual(s) with acrodysostosis (PMID: 21651393, 22464250, 28804209). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg368*) in the PRKAR1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the PRKAR1A protein. -

PRKAR1A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2024

The PRKAR1A c.1102C>T variant is predicted to result in premature protein termination (p.Arg368*). This variant has been reported as a recurrent de novo variant in patients with acrodysostosis with hormone resistance (Linglart et al. 2011. PubMed ID: 21651393; Silveira et al. 2021. PubMed ID: 34529350; Ueyama et al. 2017. PubMed ID: 28804209). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in PRKAR1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Carney complex;C1864846:Pigmented nodular adrenocortical disease, primary, 1;C3276228:Acrodysostosis 1 with or without hormone resistance Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 05-03-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.82
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906692; hg19: chr17-66526546; COSMIC: COSV56838441; COSMIC: COSV56838441;