ClinVar Genomic variation as it relates to human health
NM_182948.4(PRKACB):c.404A>T (p.His135Leu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_182948.4(PRKACB):c.404A>T (p.His135Leu)
Variation ID: 1805125 Accession: VCV001805125.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.1 1: 84184062 (GRCh38) [ NCBI UCSC ] 1: 84649745 (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 Dec 24, 2022 Dec 24, 2022 Feb 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_182948.4:c.404A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_891993.1:p.His135Leu missense NM_001242857.3:c.284A>T NP_001229786.1:p.His95Leu missense NM_001242858.3:c.227A>T NP_001229787.1:p.His76Leu missense NM_001242859.3:c.275A>T NP_001229788.1:p.His92Leu missense NM_001242860.3:c.281A>T NP_001229789.1:p.His94Leu missense NM_001242861.3:c.247-1038A>T intron variant NM_001242862.3:c.224A>T NP_001229791.1:p.His75Leu missense NM_001300915.2:c.281A>T NP_001287844.1:p.His94Leu missense NM_001300916.2:c.404A>T NP_001287845.1:p.His135Leu missense NM_001300917.2:c.227A>T NP_001287846.1:p.His76Leu missense NM_001375560.1:c.272A>T NP_001362489.1:p.His91Leu missense NM_001375561.1:c.257A>T NP_001362490.1:p.His86Leu missense NM_001375562.1:c.260A>T NP_001362491.1:p.His87Leu missense NM_001375563.1:c.251A>T NP_001362492.1:p.His84Leu missense NM_001375564.1:c.248A>T NP_001362493.1:p.His83Leu missense NM_001375565.1:c.224A>T NP_001362494.1:p.His75Leu missense NM_001375569.1:c.284A>T NP_001362498.1:p.His95Leu missense NM_001375571.1:c.281A>T NP_001362500.1:p.His94Leu missense NM_001375572.1:c.275A>T NP_001362501.1:p.His92Leu missense NM_001375573.1:c.272A>T NP_001362502.1:p.His91Leu missense NM_001375574.1:c.257A>T NP_001362503.1:p.His86Leu missense NM_001375575.1:c.272A>T NP_001362504.1:p.His91Leu missense NM_001375576.1:c.263A>T NP_001362505.1:p.His88Leu missense NM_001375577.1:c.257A>T NP_001362506.1:p.His86Leu missense NM_001375578.1:c.227A>T NP_001362507.1:p.His76Leu missense NM_001375579.1:c.224A>T NP_001362508.1:p.His75Leu missense NM_001375580.1:c.224A>T NP_001362509.1:p.His75Leu missense NM_001375581.1:c.284A>T NP_001362510.1:p.His95Leu missense NM_002731.4:c.263A>T NP_002722.1:p.His88Leu missense NM_207578.3:c.263A>T NP_997461.1:p.His88Leu missense NC_000001.11:g.84184062A>T NC_000001.10:g.84649745A>T NG_029728.1:g.111001A>T - Protein change
- H135L, H75L, H76L, H83L, H84L, H86L, H87L, H88L, H91L, H92L, H94L, H95L
- Other names
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- Canonical SPDI
- NC_000001.11:84184061:A: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
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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
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PRKACB | - | - |
GRCh38 GRCh37 |
21 | 41 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2022 | RCV002471543.1 |
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
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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
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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
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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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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardioacrofacial dysplasia 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768291.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with cardioacrofacial dysplasia 2 (MIM#619143; PMID: 33058759). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional protein kinase domain. This residue is close to the active site, and functional studies on alternative missense changes at this residue have shown it to be important for ATP-dependent response to cAMP (PMID: 33058759). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to asparagine and arginine have been reported de novo in individuals with cardioacrofacial dysplasia 2. (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband in an external laboratory (SA Path; parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome. | Palencia-Campos A | American journal of human genetics | 2020 | PMID: 33058759 |
Text-mined citations for this variant ...
HelpRecord last updated Dec 24, 2022
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.