X-18945140-G-A

Variant names:

• chrX-18945140-G-A
• rs137852294
• NM_000292.3:c.556C>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.556C>T​(p.Arg186Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000926 in 1,079,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R186H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.80
• Publications: 5 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, 4 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-18945139-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 10535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-18945140-G-A is Pathogenic according to our data. Variant chrX-18945140-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 10538.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.556C>T	p.Arg186Cys	missense_variant	Exon 6 of 33	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.556C>T	p.Arg186Cys	missense_variant	Exon 6 of 33	1	NM_000292.3	ENSP00000369274.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1079675 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 346697

African (AFR) AF: 0.00 AC: 0 AN: 26065

American (AMR) AF: 0.00 AC: 0 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19273

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 53733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 825191

Other (OTH) AF: 0.00 AC: 0 AN: 45490

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXa1 Pathogenic:2

Nov 22, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHKA2 NM_000292.2 exon 6 p.Arg186Cys (c.556C>T): This variant has been reported in the literature in at least 2 individuals with Glycogen storage disease IX (also described as X-Linked Liver Glycogenosis) (Hendrickx 1996 PMID:8733133, Davit-Spraul 2011 PMID:21646031). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:10538). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Other variants at this same codon (p.Arg186His, p.Arg186Pro) have been reported in the literature, supporting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -

Aug 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in several individuals with clinical features of glycogen storage disease (PMID: 8733133, 10330341, Invitae). ClinVar contains an entry for this variant (Variation ID: 10538). This sequence change replaces arginine with cysteine at codon 186 of the PHKA2 protein (p.Arg186Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg186 amino acid residue in PHKA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8733134, 9835437, 25266922). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Glycogen storage disease IXa2 Pathogenic:1

May 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 21, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the hemizygous state in several unrelated patients with features of a PHKA2-related disorder referred for genetic testing at GeneDx and in the published literature (Hendrickx et al., 1996; Hendrickx et al., 1999; Davit-Spraul et al., 2011) A different missense change at this residue (R186H) has been reported as likely pathogenic in ClinVar (SCV000898874.1; Landrum et al., 2016) Not observed in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.96		Loss of disorder (P = 0.0114);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.040		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: rs137852294; hg19: chrX-18963258;