rs797045008

Variant names:

• chrX-18940030-G-A
• rs797045008
• NM_000292.3:c.883C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000292.3(PHKA2):​c.883C>T​(p.Arg295Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.60
• Publications: 8 publications found

Genes affected

PHKA2 (HGNC:8926): (phosphorylase kinase regulatory subunit alpha 2) Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, and the hepatic isoform is encoded by this gene. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, which are encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9A, also known as X-linked liver glycogenosis. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.[provided by RefSeq, Feb 2010]

PHKA2 Gene-Disease associations (from GenCC):

• glycogen storage disease IXa1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• glycogen storage disease due to liver phosphorylase kinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000292.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18940029-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 803729.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-18940030-G-A is Pathogenic according to our data. Variant chrX-18940030-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3	c.883C>T	p.Arg295Cys	missense_variant	Exon 9 of 33	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.883C>T	p.Arg295Cys	missense_variant	Exon 9 of 33	1	NM_000292.3	ENSP00000369274.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1082040 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 349182

African (AFR) AF: 0.00 AC: 0 AN: 26128

American (AMR) AF: 0.00 AC: 0 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19267

East Asian (EAS) AF: 0.00 AC: 0 AN: 30129

South Asian (SAS) AF: 0.00 AC: 0 AN: 53740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40503

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 827471

Other (OTH) AF: 0.00 AC: 0 AN: 45527

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXa1 Pathogenic:2

Mar 05, 2014

Mendelics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the PHKA2 protein (p.Arg295Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GSD IXa (PMID: 12862311, 23578772, 31508908; Invitae). ClinVar contains an entry for this variant (Variation ID: 208493). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHKA2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg295 amino acid residue in PHKA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330341, 27103379, 28600779, 28627441). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Glycogen phosphorylase kinase deficiency Pathogenic:1

Aug 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PHKA2 c.883C>T (p.Arg295Cys) results in a non-conservative amino acid change located in the GH15-like domain (IPR011613) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183372 control chromosomes. c.883C>T has been reported in the literature in multiple hemizygous males affected with Glycogen Phosphorylase Kinase Deficiency (e.g., Ban_2003, Sperb-Ludwig_2019, Liang_2020, Fang_2021). These data indicate that the variant is very likely to be associated with disease. Additionally, other variants at the Arg295 residue have been reported as associated with disease (p.Arg295His), suggesting that this codon is functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 12862311, 33763395, 32772503, 31508908). ClinVar contains an entry for this variant (Variation ID: 208493). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Loss of MoRF binding (P = 0.014);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.99
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045008; hg19: chrX-18958148; COSMIC: COSV108914699;