NM_002633.3(PGM1):c.1507C>T (p.Arg503Ter) AND PGM1-congenital disorder of glycosylation

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 24, 2020
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:: RCV000032991.37

Allele description [Variation Report for NM_002633.3(PGM1):c.1507C>T (p.Arg503Ter)]

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

Gene:

PGM1:phosphoglucomutase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.3

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.63654374C>T
NG_016966.1:g.66099C>T
NM_001172818.1:c.1561C>T
NM_001172819.2:c.916C>T
NM_002633.3:c.1507C>TMANE SELECT
NP_001166289.1:p.Arg521Ter
NP_001166290.1:p.Arg306Ter
NP_002624.2:p.Arg503Ter
NC_000001.10:g.64120045C>T
NM_002633.2:c.1507C>T

Protein change:

R306*; ARG503TER

Links:

OMIM: 171900.0004; dbSNP: rs397515423

NCBI 1000 Genomes Browser:

rs397515423

Molecular consequence:

NM_001172818.1:c.1561C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001172819.2:c.916C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002633.3:c.1507C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: PGM1-congenital disorder of glycosylation
Synonyms:: CDG It; Congenital disorder of glycosylation type 1t; PHOSPHOGLUCOMUTASE 1 DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013968; MedGen: C2752015; Orphanet: 319646; OMIM: 614921

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056770	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2012)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 22492991, 33342467
SCV000996226	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001584124	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 24, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22492991, 24499211, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000056770

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2012)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000996226

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 13, 2018)

germline

clinical testing

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

SCV001584124

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 24, 2020)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots.

Conte F, Morava E, Bakar NA, Wortmann SB, Poerink AJ, Grunewald S, Crushell E, Al-Gazali L, de Vries MC, Mørkrid L, Hertecant J, Brocke Holmefjord KS, Kronn D, Feigenbaum A, Fingerhut R, Wong SY, van Scherpenzeel M, Voermans NC, Lefeber DJ.

Mol Genet Metab. 2020 Sep - Oct;131(1-2):135-146. doi: 10.1016/j.ymgme.2020.08.003. Epub 2020 Sep 17.

PubMed [citation]

PMID:: 33342467

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

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000056770.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996226.1

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

Description

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.

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

From Invitae, SCV001584124.4

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

Description

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 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). 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.

#	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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