VCV000002307.20 - ClinVar

NM_005609.4(PYGM):c.1726C>T (p.Arg576Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005609.4(PYGM):c.1726C>T (p.Arg576Ter)

Variation ID: 2307 Accession: VCV000002307.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.1 11: 64751966 (GRCh38) [ NCBI UCSC ] 11: 64519438 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 29, 2015	Jun 17, 2024	Mar 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005609.4:c.1726C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005600.1:p.Arg576Ter	nonsense
NM_001164716.1:c.1462C>T	NP_001158188.1:p.Arg488Ter	nonsense
NC_000011.10:g.64751966G>A
NC_000011.9:g.64519438G>A
NG_013018.1:g.13750C>T

... more HGVS ... less HGVS

Protein change

R576*, R488*

Other names

R575*

Canonical SPDI

NC_000011.10:64751965:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA252206 OMIM: 608455.0009 dbSNP: rs119103255 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PYGM		-	-	GRCh38 GRCh37	1345	1361

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glycogen storage disease, type V	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Mar 24, 2024	RCV000002397.25
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 17, 2023	RCV000578544.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 04, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GLYCOGEN STORAGE DISEASE V Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996068.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Comment: This stop-gained variant is predicted to result in premature truncation of the protein. This variant has been previously reported in the compound heterozygous state in … (more) This stop-gained variant is predicted to result in premature truncation of the protein. This variant has been previously reported in the compound heterozygous state in a patient with McArdle disease (PMID: 9506549). The highest reported allele frequency in the ExAC database is 0.00006 in the European (Non-Finnish) population. Based on the combined evidence, this variant is classified as pathogenic. (less) Number of individuals with the variant: 1
Likely pathogenic (Oct 29, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449611.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 2
Likely pathogenic (Jan 15, 2015)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Glycogen storage disease, type V (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000221025.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 22250184‚ 16786513‚ 9506549
Pathogenic (Apr 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type V Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809854.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Feb 17, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680730.3 First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9506549, 17404776, 34426522, 31589614, 28967462, 16786513, 17221871, 17324573, 17630210, 33726816, 34534370, 22250184, 19232494) (less)
Pathogenic (Dec 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type V Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001396085.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 8316268‚ 16786513‚ 9506549‚ 22250184 Comment: This sequence change creates a premature translational stop signal (p.Arg576) in the PYGM gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg576) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs119103255, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with McArdle disease (PMID: 9506549, 22250184). This variant is also known as Arg575Stop. ClinVar contains an entry for this variant (Variation ID: 2307). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762167.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Myopathy (present) , Rhabdomyolysis (present) , Elevated circulating creatine kinase concentration (present) , Myalgia (present) Sex: female
Pathogenic (Aug 07, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type V Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019583.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type V Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207267.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Mar 01, 1998)	no assertion criteria provided Method: literature only	MCARDLE DISEASE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022555.4 First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017	Publications: PubMed (1) PubMed: 9506549 Comment on evidence: In a patient with myophosphorylase deficiency (GSD5; 232600), Vorgerd et al. (1998) found compound heterozygosity for a nonsense mutation, arg575-to-ter (R575X), and a previously described … (more) In a patient with myophosphorylase deficiency (GSD5; 232600), Vorgerd et al. (1998) found compound heterozygosity for a nonsense mutation, arg575-to-ter (R575X), and a previously described missense mutation, G205S (608455.0002). (less)
Pathogenic (Aug 11, 2016)	no assertion criteria provided Method: research	Glycogen storage disease, type V Affected status: unknown Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536927.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017	Publications: PubMed (1) PubMed: 9506549
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Glycogen storage disease V Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001461276.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

This stop-gained variant is predicted to result in premature truncation of the protein. This variant has been previously reported in the compound heterozygous state in a patient with McArdle disease (PMID: 9506549). The highest reported allele frequency in the ExAC database is 0.00006 in the European (Non-Finnish) population. Based on the combined evidence, this variant is classified as pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9506549, 17404776, 34426522, 31589614, 28967462, 16786513, 17221871, 17324573, 17630210, 33726816, 34534370, 22250184, 19232494)

Comment:

This sequence change creates a premature translational stop signal (p.Arg576*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs119103255, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with McArdle disease (PMID: 9506549, 22250184). This variant is also known as Arg575Stop. ClinVar contains an entry for this variant (Variation ID: 2307). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry.	Lucia A	Journal of neurology, neurosurgery, and psychiatry	2012	PMID: 22250184
McArdle disease: the mutation spectrum of PYGM in a large Italian cohort.	Bruno C	Human mutation	2006	PMID: 16786513
Mutation analysis in myophosphorylase deficiency (McArdle's disease).	Vorgerd M	Annals of neurology	1998	PMID: 9506549
Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease).	Tsujino S	The New England journal of medicine	1993	PMID: 8316268

Text-mined citations for rs119103255 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005609.4(PYGM):c.1726C>T (p.Arg576Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs119103255 ...