Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.578delTG; This variant is associated with the following publications: (PMID: 35034934, 29561454, 10973256, 19429701, 19293268, 25890363, 22259056, 24088910, 30882689, 32011755)
ClinVar Genomic variation as it relates to human health
NM_002734.5(PRKAR1A):c.491_492del (p.Val164fs)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002734.5(PRKAR1A):c.491_492del (p.Val164fs)
Variation ID: 12662 Accession: VCV000012662.17
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 17q24.2 17: 68524064-68524065 (GRCh38) [ NCBI UCSC ] 17: 66520205-66520206 (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 May 3, 2013 Nov 24, 2024 Jan 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002734.5:c.491_492del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002725.1:p.Val164fs frameshift NM_001276289.2:c.491_492del NP_001263218.1:p.Val164fs frameshift NM_001276290.1:c.491_492del NP_001263219.1:p.Val164fs frameshift NM_001278433.2:c.491_492del NP_001265362.1:p.Val164fs frameshift NM_001369389.1:c.491_492del NP_001356318.1:p.Val164fs frameshift NM_001369390.1:c.491_492del NP_001356319.1:p.Val164fs frameshift NM_002734.3:c.491_492del NM_002734.3:c.491_492delTG NM_002734.4:c.491_492del NM_212471.3:c.491_492del NP_997636.1:p.Val164fs frameshift NM_212472.2:c.491_492del NP_997637.1:p.Val164fs frameshift NC_000017.11:g.68524064TG[1] NC_000017.10:g.66520205TG[1] NG_007093.3:g.115442TG[1] LRG_514:g.115442TG[1] LRG_514t2:c.491_492del LRG_514p2:p.Val164fs - Protein change
- V164fs
- Other names
-
p.Val164Aspfs*5
- Canonical SPDI
- NC_000017.11:68524063:TGTG:TG
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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.
- -
- 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. |
|||
| 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 (3) |
criteria provided, single submitter
|
Nov 1, 2023 | RCV000013498.44 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2024 | RCV000414608.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 8, 2022 | RCV002345241.10 |
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
(Feb 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490739.3
First in ClinVar: Jan 09, 2017 Last updated: Mar 11, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.578delTG; This variant is associated with the following publications: (PMID: 35034934, 29561454, 10973256, 19429701, 19293268, 25890363, 22259056, 24088910, 30882689, 32011755) (less)
|
|
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Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Carney complex, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001234247.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val164Aspfs*5) in the PRKAR1A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Val164Aspfs*5) in the PRKAR1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRKAR1A are known to be pathogenic (PMID: 11115848, 19293268). This variant is present in population databases (rs281864790, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Carney complex (PMID: 10973256, 24088910, 25890363). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as 578delTG. ClinVar contains an entry for this variant (Variation ID: 12662). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002646223.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.491_492delTG pathogenic mutation, located in coding exon 4 of the PRKAR1A gene, results from a deletion of two nucleotides at nucleotide positions 491 to … (more)
The c.491_492delTG pathogenic mutation, located in coding exon 4 of the PRKAR1A gene, results from a deletion of two nucleotides at nucleotide positions 491 to 492, causing a translational frameshift with a predicted alternate stop codon (p.V164Dfs*5). This alteration has been observed in multiple individuals who exhibit two or more of the major clinical diagnostic criteria for Carney complex (Kirschner LS et al. Nat Genet, 2000 Sep;26:89-92; Almeida MQ et al. J Clin Endocrinol Metab, 2012 Apr;97:E687-93; Briassoulis G et al. J Stroke Cerebrovasc Dis, 2012 Nov;21:914.e1-8; Havrankova E et al. Ann Thorac Cardiovasc Surg, 2014 Oct;20 Suppl:890-2; Guo H et al. World J Surg Oncol, 2015 Feb;13:83; Wang L et al. Medicine (Baltimore), 2018 Mar;97:e0247; Tirosh A et al. Horm Res Paediatr, 2018 Nov;89:38-46; Ma S et al. Medicine (Baltimore), 2019 Mar;98:e14866; Tsurutani Y et al. Intern Med, 2022 Jan;61:205-211). Loss-of-function variants subject to nonsense mediated decay (NMD) in PRKAR1A are known to cause Carney complex; however, such associations with acrodysostosis have not been reported (Michot. et al. Eur J Hum Genet 26, 1611–1622 (2018); Bertherat J et al. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91; Jafari N et al. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2024716118). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is pathogenic for Carney complex; however, the association of this alteration with acrodysostosis is unlikely. (less)
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Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413270.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1_strong, PM6, PS3, PS4_moderate, PVS1
Number of individuals with the variant: 1
|
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Pathogenic
(Sep 01, 2000)
|
no assertion criteria provided
Method: literature only
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CARNEY COMPLEX, TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033745.3
First in ClinVar: Apr 04, 2013 Last updated: May 02, 2019 |
Comment on evidence:
In affected members of 2 unrelated families with Carney complex (CNC1; 160980), Kirschner et al. (2000) identified a heterozygous 2-bp deletion (578delTG) in exon 4B … (more)
In affected members of 2 unrelated families with Carney complex (CNC1; 160980), Kirschner et al. (2000) identified a heterozygous 2-bp deletion (578delTG) in exon 4B of the PRKAR1A gene, resulting in a frameshift and premature termination of the protein before the cAMP binding domain. The families did not share the same chromosome 17 haplotype on the disease-bearing allele. The 2-bp deletion was also found in a third family and in a sporadic case. (less)
|
|
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not provided
(-)
|
no classification provided
Method: literature only
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Carney complex, type 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000058234.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2022 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Val164Aspfs*5) in the PRKAR1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRKAR1A are known to be pathogenic (PMID: 11115848, 19293268). This variant is present in population databases (rs281864790, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Carney complex (PMID: 10973256, 24088910, 25890363). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as 578delTG. ClinVar contains an entry for this variant (Variation ID: 12662). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.491_492delTG pathogenic mutation, located in coding exon 4 of the PRKAR1A gene, results from a deletion of two nucleotides at nucleotide positions 491 to 492, causing a translational frameshift with a predicted alternate stop codon (p.V164Dfs*5). This alteration has been observed in multiple individuals who exhibit two or more of the major clinical diagnostic criteria for Carney complex (Kirschner LS et al. Nat Genet, 2000 Sep;26:89-92; Almeida MQ et al. J Clin Endocrinol Metab, 2012 Apr;97:E687-93; Briassoulis G et al. J Stroke Cerebrovasc Dis, 2012 Nov;21:914.e1-8; Havrankova E et al. Ann Thorac Cardiovasc Surg, 2014 Oct;20 Suppl:890-2; Guo H et al. World J Surg Oncol, 2015 Feb;13:83; Wang L et al. Medicine (Baltimore), 2018 Mar;97:e0247; Tirosh A et al. Horm Res Paediatr, 2018 Nov;89:38-46; Ma S et al. Medicine (Baltimore), 2019 Mar;98:e14866; Tsurutani Y et al. Intern Med, 2022 Jan;61:205-211). Loss-of-function variants subject to nonsense mediated decay (NMD) in PRKAR1A are known to cause Carney complex; however, such associations with acrodysostosis have not been reported (Michot. et al. Eur J Hum Genet 26, 1611–1622 (2018); Bertherat J et al. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91; Jafari N et al. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2024716118). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is pathogenic for Carney complex; however, the association of this alteration with acrodysostosis is unlikely.
Comment:
PP1_strong, PM6, PS3, PS4_moderate, PVS1
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:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.578delTG; This variant is associated with the following publications: (PMID: 35034934, 29561454, 10973256, 19429701, 19293268, 25890363, 22259056, 24088910, 30882689, 32011755)
Comment:
This sequence change creates a premature translational stop signal (p.Val164Aspfs*5) in the PRKAR1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRKAR1A are known to be pathogenic (PMID: 11115848, 19293268). This variant is present in population databases (rs281864790, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Carney complex (PMID: 10973256, 24088910, 25890363). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as 578delTG. ClinVar contains an entry for this variant (Variation ID: 12662). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.491_492delTG pathogenic mutation, located in coding exon 4 of the PRKAR1A gene, results from a deletion of two nucleotides at nucleotide positions 491 to 492, causing a translational frameshift with a predicted alternate stop codon (p.V164Dfs*5). This alteration has been observed in multiple individuals who exhibit two or more of the major clinical diagnostic criteria for Carney complex (Kirschner LS et al. Nat Genet, 2000 Sep;26:89-92; Almeida MQ et al. J Clin Endocrinol Metab, 2012 Apr;97:E687-93; Briassoulis G et al. J Stroke Cerebrovasc Dis, 2012 Nov;21:914.e1-8; Havrankova E et al. Ann Thorac Cardiovasc Surg, 2014 Oct;20 Suppl:890-2; Guo H et al. World J Surg Oncol, 2015 Feb;13:83; Wang L et al. Medicine (Baltimore), 2018 Mar;97:e0247; Tirosh A et al. Horm Res Paediatr, 2018 Nov;89:38-46; Ma S et al. Medicine (Baltimore), 2019 Mar;98:e14866; Tsurutani Y et al. Intern Med, 2022 Jan;61:205-211). Loss-of-function variants subject to nonsense mediated decay (NMD) in PRKAR1A are known to cause Carney complex; however, such associations with acrodysostosis have not been reported (Michot. et al. Eur J Hum Genet 26, 1611–1622 (2018); Bertherat J et al. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91; Jafari N et al. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2024716118). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is pathogenic for Carney complex; however, the association of this alteration with acrodysostosis is unlikely.
Comment:
PP1_strong, PM6, PS3, PS4_moderate, PVS1
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Carney Complex. | Adam MP | - | 2023 | PMID: 20301463 |
| A Novel Missense PRKAR1A Variant Causes Carney Complex. | Kim B | Endocrinology and metabolism (Seoul, Korea) | 2022 | PMID: 36193716 |
| Carney Complex Complicated with Primary Pigmented Nodular Adrenocortical Disease without Cushing's Syndrome Recurrence for Five Years after Unilateral Adrenalectomy. | Tsurutani Y | Internal medicine (Tokyo, Japan) | 2022 | PMID: 35034934 |
| Carney complex 1 with PRKAR1A mutations manifesting as multiple repeated skin myxomas: A case report. | Sakugawa H | The Journal of dermatology | 2020 | PMID: 32011755 |
| Identification of a PRKAR1A mutation (c.491_492delTG) in familial cardiac myxoma: A case report. | Ma S | Medicine | 2019 | PMID: 30882689 |
| Recurrent left atrial myxoma in Carney complex: A case report of a familial pedigree. | Wang L | Medicine | 2018 | PMID: 29561454 |
| Failure to Thrive in the Context of Carney Complex. | Tirosh A | Hormone research in paediatrics | 2018 | PMID: 29161691 |
| Case studies of two related Chinese patients with Carney complex presenting with extensive cardiac myxomas and PRKAR1A gene mutation of c.491_492delTG. | Guo H | World journal of surgical oncology | 2015 | PMID: 25890363 |
| Carney complex with biatrial cardiac myxoma. | Havrankova E | Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia | 2014 | PMID: 24088910 |
| Recurrent left atrial myxomas in Carney complex: a genetic cause of multiple strokes that can be prevented. | Briassoulis G | Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | 2012 | PMID: 22341669 |
| Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations. | Almeida MQ | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22259056 |
| Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. | Bertherat J | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19293268 |
| Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. | Kirschner LS | Human molecular genetics | 2000 | PMID: 11115848 |
| Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. | Kirschner LS | Nature genetics | 2000 | PMID: 10973256 |
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Text-mined citations for rs281864790 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.