NM_002863.5(PYGL):c.697G>A (p.Gly233Ser) AND Glycogen storage disease, type VI

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 2, 2023
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:: RCV000989223.7

Allele description [Variation Report for NM_002863.5(PYGL):c.697G>A (p.Gly233Ser)]

NM_002863.5(PYGL):c.697G>A (p.Gly233Ser)

Gene:

PYGL:glycogen phosphorylase L [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q22.1

Genomic location:

Preferred name:

NM_002863.5(PYGL):c.697G>A (p.Gly233Ser)

HGVS:

NC_000014.9:g.50921031C>T
NG_012796.1:g.28500G>A
NM_001163940.2:c.595G>A
NM_002863.4:c.697G>A
NM_002863.5:c.697G>AMANE SELECT
NP_001157412.1:p.Gly199Ser
NP_002854.3:p.Gly233Ser
NC_000014.8:g.51387749C>T

Protein change:

G199S

Links:

dbSNP: rs749922511

NCBI 1000 Genomes Browser:

rs749922511

Molecular consequence:

NM_001163940.2:c.595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002863.5:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glycogen storage disease, type VI (GSD6)
Synonyms:: GSD VI; Glycogen storage disease type 6; Hers disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009294; MedGen: C0017925; Orphanet: 369; OMIM: 232700

Recent activity

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txid1801697[Organism] (1)
BioSample
Metagenome or environmental sample from Nitrospirae bacterium GWC2_57_13
Metagenome or environmental sample from Nitrospirae bacterium GWC2_57_13

biosample
SAMN06169700 (1)
SRA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001139456	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001534458	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 18, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12809646, 31508908, 28492532
SCV004038082	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31508908, 34026552, 32892177 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001139456

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Pathogenic
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV001534458

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 18, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004038082

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 2, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel mutation (G233D) in the glycogen phosphorylase gene in a patient with hepatic glycogen storage disease and residual enzyme activity.

Tang NL, Hui J, Young E, Worthington V, To KF, Cheung KL, Li CK, Fok TF.

Mol Genet Metab. 2003 Jun;79(2):142-5.

PubMed [citation]

PMID:: 12809646

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (5)

Details of each submission

From Mendelics, SCV001139456.1

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

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

From Invitae, SCV001534458.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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. This variant disrupts the p.Gly233 amino acid residue in PYGL. Other variant(s) that disrupt this residue have been observed in individuals with PYGL-related conditions (PMID: 12809646; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 499130). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 31508908; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs749922511, ExAC 0.01%). This sequence change replaces glycine with serine at codon 233 of the PYGL protein (p.Gly233Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038082.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: PYGL c.697G>A (p.Gly233Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes (gnomAD). c.697G>A has been reported in the literature in individuals affected with Glycogen storage disease, type VI (examples: Sperb-Ludwig_2019, Lu_2020, and Grunert_2021). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same residue (p.Gly233Asp) has been classified as pathogenic in ClinVar suggesting this residue may be functionally important (CV ID 21339). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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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