rs397515330

chr10-51467819-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_006258.4(PRKG1):c.575G>A(p.Arg192Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.59

Genes affected

PRKG1 (HGNC:9414): (protein kinase cGMP-dependent 1) Mammals have three different isoforms of cyclic GMP-dependent protein kinase (Ialpha, Ibeta, and II). These PRKG isoforms act as key mediators of the nitric oxide/cGMP signaling pathway and are important components of many signal transduction processes in diverse cell types. This PRKG1 gene on human chromosome 10 encodes the soluble Ialpha and Ibeta isoforms of PRKG by alternative transcript splicing. A separate gene on human chromosome 4, PRKG2, encodes the membrane-bound PRKG isoform II. The PRKG1 proteins play a central role in regulating cardiovascular and neuronal functions in addition to relaxing smooth muscle tone, preventing platelet aggregation, and modulating cell growth. This gene is most strongly expressed in all types of smooth muscle, platelets, cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. Isoforms Ialpha and Ibeta have identical cGMP-binding and catalytic domains but differ in their leucine/isoleucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKG1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 10-51467819-G-A is Pathogenic according to our data. Variant chr10-51467819-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-51467819-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_006258.4	c.575G>A	p.Arg192Gln	missense_variant	3/18	ENST00000373980.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000373980.11	c.575G>A	p.Arg192Gln	missense_variant	3/18	1	NM_006258.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459940 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726356

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 8 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 08, 2013	- -
Pathogenic, criteria provided, single submitter	research	Department of Internal Medicine, University of Texas Health Science Center at Houston	Jan 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 192 of the PRKG1 protein (p.Arg192Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thoracic aortic aneurysms and acute aortic dissection (PMID: 23910461, 27442293). It has also been observed to segregate with disease in related individuals. This variant is also known as c.530G>A (p.Arg177Gln). ClinVar contains an entry for this variant (Variation ID: 65477). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PRKG1 function (PMID: 23910461). For these reasons, this variant has been classified as Pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2022	The p.R192Q pathogenic mutation (also known as c.575G>A and p.R177Q), located in coding exon 3 of the PRKG1 gene, results from a G to A substitution at nucleotide position 575. The arginine at codon 192 is replaced by glutamine, an amino acid with highly similar properties. This mutation (described as p.R177Q) was shown to segregate with aortic disease in four families; cell functional studies suggested that the alteration affected cGMP binding and resulted in a kinase whose activity is no longer modulated by cGMP, thereby resulting in a gain-of-function effect (Guo DC et al, Am. J. Hum. Genet. 2013 Aug; 93:398-404). This alteration, again referred to as p.R177Q, has also been reported in additional individuals and another large family affected with aortic disease (Gago-Díaz M. Eur. J. Clin. Invest. 2016 Sep;46:787-94; Hicks KL et al. J Vasc Surg, 2018 09;68:701-711; Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2019	The p.Arg192Gln (referred to as p.Arg177Gln) variant in PRKG1 has been reported in 6 individuals with thoracic aortic disease and segregated with disease in 22 affected individuals from 5 families (Guo 2103, Gago-Diaz 2016, Overwated 2018) and in ClinVar (Variation ID 65477). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function, suggesting gain of function is the mechanism of disease (Guo 2013). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant thoracic aortic disease. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3, PS3_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2021

Observed in patients with TAAD referred for genetic testing at GeneDx and in the published literature (Guo et al., 2013; Gago-Diaz et al., 2016; Overwater et al., 2018; Wolford et al., 2019; Shalhub et al., 2019); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated a gain-of-function effect in which p.(R192Q) led to a constitutively active type I cGMP-dependent protein kinase, causing decreased phosphorylation of the myosin regulatory light chain in fibroblasts and thereby decreased contraction of vascular smooth muscle cells (Guo et al., 2013; Chan et al., 2020); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 65477; Landrum et al., 2016); Also known as R177Q; This variant is associated with the following publications: (PMID: 31211624, 23910461, 27442293, 29907982, 27879251, 29510914, 32506052, 30871887) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;.;.;.;D;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.;.;.;D;.;.;.
Polyphen		1.0	D;D;.;D;D;.;.;.
Vest4		0.91, 0.94
MutPred		0.89		Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);.;.;.;.;.;.;
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397515330; hg19: chr10-53227579;