NM_000292.3(PHKA2):c.559G>A (p.Gly187Arg) AND Glycogen storage disease IXa1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001940035.3

Allele description [Variation Report for NM_000292.3(PHKA2):c.559G>A (p.Gly187Arg)]

NM_000292.3(PHKA2):c.559G>A (p.Gly187Arg)

Gene:

PHKA2:phosphorylase kinase regulatory subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp22.13

Genomic location:

Preferred name:

NM_000292.3(PHKA2):c.559G>A (p.Gly187Arg)

HGVS:

NC_000023.11:g.18945137C>T
NG_016622.1:g.44226G>A
NM_000292.3:c.559G>AMANE SELECT
NP_000283.1:p.Gly187Arg
NC_000023.10:g.18963255C>T

Protein change:

G187R

Links:

dbSNP: rs2147972085

NCBI 1000 Genomes Browser:

rs2147972085

Molecular consequence:

NM_000292.3:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glycogen storage disease IXa1
Synonyms:: LIVER GLYCOGENOSIS, X-LINKED, TYPE I; GSD VIII; Glycogen storage disease 8; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010598; MedGen: C3694531; Orphanet: 264580; OMIM: 306000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002177969	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21646031, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002177969

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 23, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Liver glycogen storage diseases due to phosphorylase system deficiencies: diagnosis thanks to non invasive blood enzymatic and molecular studies.

Davit-Spraul A, Piraud M, Dobbelaere D, Valayannopoulos V, Labrune P, Habes D, Bernard O, Jacquemin E, Baussan C.

Mol Genet Metab. 2011 Sep-Oct;104(1-2):137-43. doi: 10.1016/j.ymgme.2011.05.010. Epub 2011 May 17.

PubMed [citation]

PMID:: 21646031

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002177969.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 1410249). This missense change has been observed in individuals with Glycogen storage disease (PMID: 21646031; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 187 of the PHKA2 protein (p.Gly187Arg).

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

Last Updated: Feb 20, 2024

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