VCV000039772.17 - ClinVar

NM_002633.3(PGM1):c.1507C>T (p.Arg503Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (4)

4 out of 5 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002633.3(PGM1):c.1507C>T (p.Arg503Ter)

Variation ID: 39772 Accession: VCV000039772.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 63654374 (GRCh38) [ NCBI UCSC ] 1: 64120045 (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	Aug 16, 2015	May 30, 2026	Nov 11, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_002633.3:c.1507C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002624.2:p.Arg503Ter	nonsense
NM_001172818.1:c.1561C>T	NP_001166289.1:p.Arg521Ter	nonsense
NM_001172819.2:c.916C>T	NP_001166290.1:p.Arg306Ter	nonsense
NC_000001.11:g.63654374C>T
NC_000001.10:g.64120045C>T
NG_016966.1:g.66099C>T

... more HGVS ... less HGVS

Protein change

R503*, R521*, R306*

Other names

Canonical SPDI

NC_000001.11:63654373:C:T

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

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA130546 OMIM: 171900.0004 dbSNP: rs397515423 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.
PGM1		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	453	566

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.
PGM1-congenital disorder of glycosylation	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 24, 2020	RCV000032991.40
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 11, 2025	RCV004719669.2

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.	Expand all rows Collapse all rows 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 (Dec 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	CONGENITAL DISORDER OF GLYCOSYLATION, TYPE It	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996226.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Comment: show This nonsense variant found in exon 10 of 11 is predicted to result in loss of normal protein function. This variant has been previously reported as a homozygous change in two patients with Pierre Robin sequence, cleft palate, tachycardia, dilated cardiomyopathy, elevated creatine kinase, and elevated liver enzymes (PMID: 22492991, 24499211) and as a compound heterozygous change in trans with c.1172G>T p.Gly391Val in one patient with hypoglycemia, cleft palate, micrognathia, delayed speech development, elevated liver enzymes, and mild enlargment of the left ventricle (PMID: 29858906). Functional characterization of fibroblasts from both patients with a homozygous change demonstrated phosphoglucomutase activity of 7-8% as compared to controls (PMID: 22492991). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0012% (3/251206) and thus is presumed to be rare. Based on the available evidence, the c.1561C>T p.Arg521Ter variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Pathogenic (Dec 24, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	PGM1-congenital disorder of glycosylation	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001584124.6 First in ClinVar: May 10, 2021 Last updated: Mar 07, 2026	Publications: PubMed (2) PubMed: 22492991‚ 24499211 Comment: show This variant has been observed in individual(s) with PGM1-congenital disorder of glycosylation (PMID: 22492991, 24499211). ClinVar contains an entry for this variant (Variation ID: 39772). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PGM1 are known to be pathogenic (PMID: 22492991). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg503*) in the PGM1 gene. It is expected to result in an absent or disrupted protein product. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005325045.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: show 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36007526, 24499211, 22492991, 29858906) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (DASA Assertion Criteria)	not provided	Dasa Accession: SCV007598168.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Publications: PubMed (4) PubMed: 22492991‚ 24499211‚ 29858906‚ 33342467 Comment: show NM_002633.3(PGM1):c.1507C>T (p.Arg503*) introduces a premature termination codon predicted to result in loss of normal protein function. Loss-of-function is an established mechanism of disease for this gene. This variant has been observed in affected individuals with related phenotype in a genotype context consistent with recessive disease (PMID: 22492991; PMID: 24499211; PMID: 33342467; PMID: 29858906). This variant has been recurrently observed in individuals with related phenotype (PMID: 22492991; PMID: 24499211; PMID: 33342467; PMID: 29858906). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 01, 2012) N Not contributing to aggregate classification	no assertion criteria provided	CONGENITAL DISORDER OF GLYCOSYLATION, TYPE It	OMIM Accession: SCV000056770.4 First in ClinVar: Apr 04, 2013 Last updated: Apr 24, 2021	Publications: PubMed (2) PubMed: 22492991‚ 33342467 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a 16-year-old girl with congenital disorder of glycosylation type It (CDG1T; 614921), Timal et al. (2012) identified a homozygous 1507C-T transition in the PGM1 … (more) In a 16-year-old girl with congenital disorder of glycosylation type It (CDG1T; 614921), Timal et al. (2012) identified a homozygous 1507C-T transition in the PGM1 gene, resulting in an arg503-to-ter (R503X) substitution and a truncated protein lacking the last 60 amino acids. Each unaffected parent was heterozygous for the mutation. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. The patient had Pierre Robin sequence with cleft palate, chronic hepatitis, fatigue and dyspnea, and dilated cardiomyopathy. Laboratory studies showed elevated liver enzymes and increased serum creatine kinase. Studies in patient fibroblasts showed 8% residual enzyme activity. In an Australian patient (patient 2) with CDG1T, Conte et al. (2020) identified compound heterozygous mutations in the PGM1 gene: R503X and an indel mutation (c.157_158delinsG; 171900.0010), predicted to result in a frameshift and premature termination (Gln53GlyfsTer15). The mutations were identified by PGM1 gene sequencing, and the parents were confirmed to be carriers. Functional studies were not performed. (less)

Comment:

This nonsense variant found in exon 10 of 11 is predicted to result in loss of normal protein function. This variant has been previously reported as a homozygous change in two patients with Pierre Robin sequence, cleft palate, tachycardia, dilated cardiomyopathy, elevated creatine kinase, and elevated liver enzymes (PMID: 22492991, 24499211) and as a compound heterozygous change in trans with c.1172G>T p.Gly391Val in one patient with hypoglycemia, cleft palate, micrognathia, delayed speech development, elevated liver enzymes, and mild enlargment of the left ventricle (PMID: 29858906). Functional characterization of fibroblasts from both patients with a homozygous change demonstrated phosphoglucomutase activity of 7-8% as compared to controls (PMID: 22492991). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0012% (3/251206) and thus is presumed to be rare. Based on the available evidence, the c.1561C>T p.Arg521Ter variant is classified as pathogenic.

Comment:

This variant has been observed in individual(s) with PGM1-congenital disorder of glycosylation (PMID: 22492991, 24499211). ClinVar contains an entry for this variant (Variation ID: 39772). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PGM1 are known to be pathogenic (PMID: 22492991). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg503*) in the PGM1 gene. It is expected to result in an absent or disrupted protein product.

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36007526, 24499211, 22492991, 29858906)

Comment:

NM_002633.3(PGM1):c.1507C>T (p.Arg503*) introduces a premature termination codon predicted to result in loss of normal protein function. Loss-of-function is an established mechanism of disease for this gene. This variant has been observed in affected individuals with related phenotype in a genotype context consistent with recessive disease (PMID: 22492991; PMID: 24499211; PMID: 33342467; PMID: 29858906). This variant has been recurrently observed in individuals with related phenotype (PMID: 22492991; PMID: 24499211; PMID: 33342467; PMID: 29858906). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots.	Conte F	Molecular genetics and metabolism	2020	PMID: 33342467
Clinical and molecular genetic characterization of two patients with mutations in the phosphoglucomutase 1 (PGM1) gene.	Ding Y	Journal of pediatric endocrinology & metabolism : JPEM	2018	PMID: 29858906
Multiple phenotypes in phosphoglucomutase 1 deficiency.	Tegtmeyer LC	The New England journal of medicine	2014	PMID: 24499211
Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.	Timal S	Human molecular genetics	2012	PMID: 22492991

Text-mined citations for rs397515423 ...

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 Jun 06, 2026