rs1555815121

Positions:

• chr17-68530306-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002734.5(PRKAR1A):​c.1003C>T​(p.Arg335Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAR1A NM_002734.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.01

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 19 ACMG points.

• PM1: In a binding_site (size 126) in uniprot entity KAP0_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002734.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKAR1A. . Gene score misZ 3.1236 (greater than the threshold 3.09). Trascript score misZ 4.1467 (greater than threshold 3.09). GenCC has associacion of gene with acrodysostosis with multiple hormone resistance, pigmented nodular adrenocortical disease, primary, 1, primary pigmented nodular adrenocortical disease, acrodysostosis, Carney complex, Acrodysostosis 1 with or without hormone resistance, Carney complex, type 1, familial atrial myxoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 17-68530306-C-T is Pathogenic according to our data. Variant chr17-68530306-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.1003C>T	p.Arg335Cys	missense_variant	11/11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.1003C>T	p.Arg335Cys	missense_variant	11/11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrodysostosis 1 with or without hormone resistance Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Jan 12, 2016

- -

Pigmented nodular adrenocortical disease, primary, 1;C2607929:Carney complex, type 1;C2931787:Familial atrial myxoma;C3276228:Acrodysostosis 1 with or without hormone resistance Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2022

Observed in individuals with acrodysostosis (Muhn et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26763073, 27535533, 23425300, 24363928) -

Carney complex, type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg335 amino acid residue in PRKAR1A. Other variant(s) that disrupt this residue have been observed in individuals with PRKAR1A-related conditions (PMID: 22464252, 23043190), which suggests that this may be a clinically significant amino acid residue. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PRKAR1A function. ClinVar contains an entry for this variant (Variation ID: 433148). This missense change has been observed in individual(s) with acrodysostosis (PMID: 23425300). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 335 of the PRKAR1A protein (p.Arg335Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D;D;.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.81
MutPred		0.79		Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);
MVP		0.97
MPC		2.9
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1555815121; hg19: chr17-66526447;