VCV002137130.3 - ClinVar

NM_005609.4(PYGM):c.1769G>A (p.Arg590His)

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.

(2)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005609.4(PYGM):c.1769G>A (p.Arg590His)

Variation ID: 2137130 Accession: VCV002137130.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.1 11: 64751655 (GRCh38) [ NCBI UCSC ] 11: 64519127 (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	Feb 8, 2023	Jun 17, 2024	Mar 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005609.4:c.1769G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005600.1:p.Arg590His	missense
NM_001164716.1:c.1505G>A	NP_001158188.1:p.Arg502His	missense
NC_000011.10:g.64751655C>T
NC_000011.9:g.64519127C>T
NG_013018.1:g.14061G>A

... more HGVS ... less HGVS

Protein change

R502H, R590H

Other names

Canonical SPDI

NC_000011.10:64751654:C:T

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.

Links

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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Mar 28, 2024	RCV003062396.5

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.
Uncertain significance (Jan 17, 2022)	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: SCV003439880.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (3) PubMed: 17324573‚ 22250184‚ 29143597 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the PYGM protein (p.Arg590His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the PYGM protein (p.Arg590His). This variant is present in population databases (rs115942812, gnomAD 0.01%). This missense change has been observed in individual(s) with myophosphorylase deficiency (McArdle disease) (PMID: 17324573, 22250184, 29143597). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. 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. (less)
Likely pathogenic (Mar 28, 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: SCV004207204.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the PYGM protein (p.Arg590His). This variant is present in population databases (rs115942812, gnomAD 0.01%). This missense change has been observed in individual(s) with myophosphorylase deficiency (McArdle disease) (PMID: 17324573, 22250184, 29143597). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. 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.

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 all Spanish patients with McArdle disease: a 2016 update.	Santalla A	BMC genomics	2017	PMID: 29143597
Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry.	Lucia A	Journal of neurology, neurosurgery, and psychiatry	2012	PMID: 22250184
Molecular characterization of myophosphorylase deficiency (McArdle disease) in 34 patients from Southern France: identification of 10 new mutations. Absence of genotype-phenotype correlation.	Aquaron R	Neuromuscular disorders : NMD	2007	PMID: 17324573

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005609.4(PYGM):c.1769G>A (p.Arg590His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...