NM_182948.4(PRKACB):c.844G>C (p.Gly282Arg) AND Cardioacrofacial dysplasia 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 28, 2020
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001271115.1

Allele description [Variation Report for NM_182948.4(PRKACB):c.844G>C (p.Gly282Arg)]

NM_182948.4(PRKACB):c.844G>C (p.Gly282Arg)

Gene:

PRKACB:protein kinase cAMP-activated catalytic subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_182948.4(PRKACB):c.844G>C (p.Gly282Arg)

HGVS:

NC_000001.11:g.84202743G>C
NG_029728.1:g.129682G>C
NM_001242857.3:c.724G>C
NM_001242858.3:c.667G>C
NM_001242859.3:c.715G>C
NM_001242860.3:c.721G>C
NM_001242861.3:c.613G>C
NM_001242862.3:c.664G>C
NM_001300915.2:c.721G>C
NM_001300916.2:c.844G>C
NM_001300917.2:c.667G>C
NM_001375560.1:c.712G>C
NM_001375561.1:c.697G>C
NM_001375562.1:c.700G>C
NM_001375563.1:c.691G>C
NM_001375564.1:c.688G>C
NM_001375565.1:c.664G>C
NM_001375569.1:c.724G>C
NM_001375571.1:c.721G>C
NM_001375572.1:c.715G>C
NM_001375573.1:c.712G>C
NM_001375574.1:c.697G>C
NM_001375575.1:c.712G>C
NM_001375576.1:c.703G>C
NM_001375577.1:c.697G>C
NM_001375578.1:c.667G>C
NM_001375579.1:c.664G>C
NM_001375580.1:c.664G>C
NM_001375581.1:c.724G>C
NM_002731.4:c.703G>C
NM_182948.4:c.844G>CMANE SELECT
NM_207578.3:c.703G>C
NP_001229786.1:p.Gly242Arg
NP_001229787.1:p.Gly223Arg
NP_001229788.1:p.Gly239Arg
NP_001229789.1:p.Gly241Arg
NP_001229790.1:p.Gly205Arg
NP_001229791.1:p.Gly222Arg
NP_001287844.1:p.Gly241Arg
NP_001287845.1:p.Gly282Arg
NP_001287846.1:p.Gly223Arg
NP_001362489.1:p.Gly238Arg
NP_001362490.1:p.Gly233Arg
NP_001362491.1:p.Gly234Arg
NP_001362492.1:p.Gly231Arg
NP_001362493.1:p.Gly230Arg
NP_001362494.1:p.Gly222Arg
NP_001362498.1:p.Gly242Arg
NP_001362500.1:p.Gly241Arg
NP_001362501.1:p.Gly239Arg
NP_001362502.1:p.Gly238Arg
NP_001362503.1:p.Gly233Arg
NP_001362504.1:p.Gly238Arg
NP_001362505.1:p.Gly235Arg
NP_001362506.1:p.Gly233Arg
NP_001362507.1:p.Gly223Arg
NP_001362508.1:p.Gly222Arg
NP_001362509.1:p.Gly222Arg
NP_001362510.1:p.Gly242Arg
NP_002722.1:p.Gly235Arg
NP_891993.1:p.Gly282Arg
NP_997461.1:p.Gly235Arg
NC_000001.10:g.84668426G>C
NM_002731.3:c.703G>C

Protein change:

G205R; GLY235ARG

Links:

OMIM: 176892.0001; dbSNP: rs1670492319

NCBI 1000 Genomes Browser:

rs1670492319

Molecular consequence:

NM_001242857.3:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242858.3:c.667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242859.3:c.715G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242860.3:c.721G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242861.3:c.613G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242862.3:c.664G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001300915.2:c.721G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001300916.2:c.844G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001300917.2:c.667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375560.1:c.712G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375561.1:c.697G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375562.1:c.700G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375563.1:c.691G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375564.1:c.688G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375565.1:c.664G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375569.1:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375571.1:c.721G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375572.1:c.715G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375573.1:c.712G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375574.1:c.697G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375575.1:c.712G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375576.1:c.703G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375577.1:c.697G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375578.1:c.667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375579.1:c.664G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375580.1:c.664G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375581.1:c.724G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002731.4:c.703G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_182948.4:c.844G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_207578.3:c.703G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardioacrofacial dysplasia 2
Identifiers:: MONDO: MONDO:0030877; MedGen: C5436886; OMIM: 619143

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001451959	OMIM	no assertion criteria provided	Pathogenic (Dec 28, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001451959

OMIM

no assertion criteria provided

Pathogenic
(Dec 28, 2020)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.

Palencia-Campos A, Aoto PC, Machal EMF, Rivera-Barahona A, Soto-Bielicka P, Bertinetti D, Baker B, Vu L, Piceci-Sparascio F, Torrente I, Boudin E, Peeters S, Van Hul W, Huber C, Bonneau D, Hildebrand MS, Coleman M, Bahlo M, Bennett MF, Schneider AL, Scheffer IE, Kibæk M, et al.

Am J Hum Genet. 2020 Nov 5;107(5):977-988. doi: 10.1016/j.ajhg.2020.09.005. Epub 2020 Oct 14.

PubMed [citation]

PMID:: 33058759
PMCID:: PMC7675002

Details of each submission

From OMIM, SCV001451959.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an 18-year-old Danish woman (P4) with cardioacrofacial dysplasia (CAFD2; 619143), Palencia-Campos et al. (2020) identified heterozygosity for a de novo c.703G-C transversion (c.703G-C, NM_002731.3) in the PRKACB gene, resulting in a gly235-to-arg (G235R) substitution at a highly conserved residue at a tethering surface that interacts with regulatory proteins. The mutation was not found in the gnomAD database. Bioluminescence resonance energy transfer analysis showed a dramatic increase in sensitivity to cAMP with the mutant holoenzyme compared to the wildtype PKA holoenzyme, and PepTag assay in transfected HEK293 cells showed increased kinase activity with the G235R mutant at low cAMP concentrations compared to wildtype protein. Analysis of hedgehog (see 600725) pathway signaling in retrotransduced NIH 3T3 cells after stimulation with the SMO (601500) agonist SAG revealed that the G235R mutant impairs SAG-mediated inactivation of PKA.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 23, 2022

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