NM_000292.3(PHKA2):c.772G>A (p.Gly258Arg) AND Glycogen storage disease IXa1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 26, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002243544.4

Allele description [Variation Report for NM_000292.3(PHKA2):c.772G>A (p.Gly258Arg)]

NM_000292.3(PHKA2):c.772G>A (p.Gly258Arg)

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.772G>A (p.Gly258Arg)

HGVS:

NC_000023.11:g.18941621C>T
NG_016622.1:g.47742G>A
NM_000292.3:c.772G>AMANE SELECT
NP_000283.1:p.Gly258Arg
NC_000023.10:g.18959739C>T

Protein change:

G258R

Links:

dbSNP: rs2147962993

NCBI 1000 Genomes Browser:

rs2147962993

Molecular consequence:

NM_000292.3:c.772G>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
SCV002512213	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003321612	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002512213

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 5, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003321612

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 26, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512213.1

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

Description

ACMG classification criteria: PM2 moderate, PP3 supporting

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

From Invitae, SCV003321612.2

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 1683501). This missense change has been observed in individual(s) with clinical features of glycogen storage disease type IXa (Invitae). 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 258 of the PHKA2 protein (p.Gly258Arg).

#	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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