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.
ClinVar Genomic variation as it relates to human health
NM_002734.5(PRKAR1A):c.1102C>T (p.Arg368Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(12)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002734.5(PRKAR1A):c.1102C>T (p.Arg368Ter)
Variation ID: 29907 Accession: VCV000029907.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q24.2 17: 68530405 (GRCh38) [ NCBI UCSC ] 17: 66526546 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 22, 2016 Oct 8, 2024 Jan 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002734.5:c.1102C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002725.1:p.Arg368Ter nonsense NM_001276289.2:c.1102C>T NP_001263218.1:p.Arg368Ter nonsense NM_001276290.1:c.973+404C>T intron variant NM_001278433.2:c.1102C>T NP_001265362.1:p.Arg368Ter nonsense NM_001369389.1:c.1102C>T NP_001356318.1:p.Arg368Ter nonsense NM_001369390.1:c.1102C>T NP_001356319.1:p.Arg368Ter nonsense NM_212471.3:c.1102C>T NP_997636.1:p.Arg368Ter nonsense NM_212472.2:c.1102C>T NP_997637.1:p.Arg368Ter nonsense NC_000017.11:g.68530405C>T NC_000017.10:g.66526546C>T NG_007093.3:g.121783C>T LRG_514:g.121783C>T LRG_514t1:c.1102C>T LRG_514p1:p.Arg368Ter LRG_514t2:c.1102C>T LRG_514p2:p.Arg368Ter - Protein change
- R368*
- Other names
- -
- Canonical SPDI
- NC_000017.11:68530404:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| PRKAR1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1078 | 1332 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2021 | RCV000022791.32 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2023 | RCV000760318.7 | |
| not provided (1) |
no classification provided
|
- | RCV001824573.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2022 | RCV001852002.4 | |
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PRKAR1A-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Apr 4, 2024 | RCV003398560.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Mar 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Acrodysostosis 1 with or without hormone resistance
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001786630.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001832501.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Acrodysostosis 1 with or without hormone resistance
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013552.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Fetal growth restriction (present) , Intellectual disability, mild (present) , Congenital hypothyroidism (present) , Macrodontia of permanent maxillary central incisor (present) , Short finger (present) … (more)
Fetal growth restriction (present) , Intellectual disability, mild (present) , Congenital hypothyroidism (present) , Macrodontia of permanent maxillary central incisor (present) , Short finger (present) , Short toe (present) , Short palm (present) , Short foot (present) , Short finger (present) , Short toe (present) , Wide nasal base (present) , Short stature (present) , Short metacarpal (present) , Broad metacarpals (present) , Short metatarsal (present) , Elevated circulating parathyroid hormone level (present) (less)
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Acrodysostosis 1 with or without hormone resistance
Affected status: yes
Allele origin:
de novo
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001156417.1
First in ClinVar: Feb 15, 2020 Last updated: Feb 15, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Hydrops fetalis (present) , Neonatal hypotonia (present) , Global developmental delay (present) , Abnormal facial shape (present) , Cryptorchidism (present) , Brachycephaly (present) , Microcornea … (more)
Hydrops fetalis (present) , Neonatal hypotonia (present) , Global developmental delay (present) , Abnormal facial shape (present) , Cryptorchidism (present) , Brachycephaly (present) , Microcornea (present) (less)
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Pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Acrodysostosis 1 with or without hormone resistance
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767741.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Jan 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000890174.2
First in ClinVar: Mar 19, 2019 Last updated: May 06, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Carney complex, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002244612.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Apr 06, 2012)
|
no assertion criteria provided
Method: literature only
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ACRODYSOSTOSIS 1 WITH HORMONE RESISTANCE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044080.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 3 unrelated patients with acrodysostosis-1 with hormone resistance (ACRDYS1; 101800), Linglart et al. (2011) identified a de novo heterozygous 1101C-T transition in exon 11 … (more)
In 3 unrelated patients with acrodysostosis-1 with hormone resistance (ACRDYS1; 101800), Linglart et al. (2011) identified a de novo heterozygous 1101C-T transition in exon 11 of the PRKAR1A gene, resulting in an arg368-to-ter (R368X) substitution predicted to result in absence of the cAMP-binding domain B. The mutation was not found in 200 control samples. Patient cells showed decreased protein kinase A activity compared to controls. In vitro functional expression studies showed that the mutant protein had decreased cAMP-induced activation of protein kinase A compared to wildtype. Bioluminescent studies showed that the mutant regulatory PRKAR1A subunits were able to bind protein kinase A catalytic subunits, but were insensitive to dissociation in response to cAMP. Finally, 3-dimensional models indicated that the R368X mutation would lead to abnormalities in the domain B pocket that would preclude high-affinity binding of cAMP. Linglart et al. (2011) concluded that this was a gain-of-function mutation that decreased protein kinase A sensitivity to cAMP. The 3 patients had short stature, peripheral dysostosis, nasal and maxillary hypoplasia, severe brachydactyly, epiphyseal stippling, and advanced bone age. Serum parathyroid hormone was markedly increased, but calcium was normal. All had evidence of multiple hormone resistance, including thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. Linglart et al. (2011) stated that the mutation resulted in an impairment of protein kinase A activity, not total absence, which may have resulted in variation in the extent to hormone resistance depending on cell-specific expression of alternative protein kinase A isoforms. Michot et al. (2012) identified a heterozygous de novo R368X mutation in 4 unrelated patients with acrodysostosis with hormone resistance. The patients had short stature, severe brachydactyly, short metatarsals, metacarpals, and phalanges, and cone-shaped epiphyses in childhood. Only 2 had mild facial dysostosis and all had normal intellect. All had evidence of hormone resistance, with increased PTH and TSH and clinical hypothyroidism. (less)
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797880.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(Apr 04, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PRKAR1A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120846.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955519.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Carney complex
Pigmented nodular adrenocortical disease, primary, 1 Acrodysostosis 1 with or without hormone resistance
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
de novo
|
GenomeConnect, ClinGen
Accession: SCV002075128.2
First in ClinVar: Feb 12, 2022 Last updated: Jun 17, 2024 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormal placenta morphology (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Encephalopathy (present) , Generalized … (more)
Abnormal placenta morphology (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Encephalopathy (present) , Generalized hypotonia (present) , Movement disorder (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal esophagus morphology (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2021-05-03
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
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.
Comment:
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
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Endocrinological and phenotype evaluation in a patient with acrodysostosis. | Ueyama K | Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology | 2017 | PMID: 28804209 |
| Knock-In of the Recurrent R368X Mutation of PRKAR1A that Represses cAMP-Dependent Protein Kinase A Activation: A Model of Type 1 Acrodysostosis. | Le Stunff C | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2017 | PMID: 27589370 |
| Functional Characterization of PRKAR1A Mutations Reveals a Unique Molecular Mechanism Causing Acrodysostosis but Multiple Mechanisms Causing Carney Complex. | Rhayem Y | The Journal of biological chemistry | 2015 | PMID: 26405036 |
| PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. | Linglart A | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 23043190 |
| Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. | Michot C | American journal of human genetics | 2012 | PMID: 22464250 |
| Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. | Linglart A | The New England journal of medicine | 2011 | PMID: 21651393 |
Text-mined citations for rs387906692 ...
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Record last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.