NM_000291.4(PGK1):c.639C>T (p.Gly213=) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 4, 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:: RCV000492963.11

Allele description [Variation Report for NM_000291.4(PGK1):c.639C>T (p.Gly213=)]

NM_000291.4(PGK1):c.639C>T (p.Gly213=)

Gene:

PGK1:phosphoglycerate kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq21.1

Genomic location:

Preferred name:

NM_000291.4(PGK1):c.639C>T (p.Gly213=)

HGVS:

NC_000023.11:g.78118168C>T
NG_008862.1:g.19000C>T
NM_000291.4:c.639C>TMANE SELECT
NP_000282.1:p.Gly213=
NC_000023.10:g.77373665C>T
NM_000291.3:c.639C>T
NP_000282.1:p.(=)

Links:

dbSNP: rs797044505

NCBI 1000 Genomes Browser:

rs797044505

Molecular consequence:

NM_000291.4:c.639C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581930	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (May 7, 2018)	germline	clinical testing	Citation Link,
SCV004300120	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30111548, 17661373, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581930

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(May 7, 2018)

germline

clinical testing

Citation Link,

SCV004300120

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

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	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.

Vissing J, Akman HO, Aasly J, Kahler SG, Bacino CA, DiMauro S, Haller RG.

Neurology. 2018 Sep 11;91(11):e1077-e1082. doi: 10.1212/WNL.0000000000006165. Epub 2018 Aug 15.

PubMed [citation]

PMID:: 30111548

Altered expression of PGK1 in a family with phosphoglycerate kinase deficiency.

Svaasand EK, Aasly J, Landsem VM, Klungland H.

Muscle Nerve. 2007 Nov;36(5):679-84.

PubMed [citation]

PMID:: 17661373

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000203250.7

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000581930.4

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

Description

The c.639C>T variant in the PGK1 gene has been reported previously in two brothers with phosphoglycerate kinase deficiency. They presented with muscle pain, cramps, and stiffness following heavy exercise. Their sister, who was heterozygous for the c.639C>T mutation, also experienced mild muscle stiffness during exercise (Svaasand et al., 2007). This splicing variant, which also results in a synonymous change (p.Gly213Gly), is predicted to destroy the canonical splice donor site in intron 6. The c.639C>T variant is predicted to induce a large splicing change (Xiong et al., 2014). The c.639C>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.639C>T variant is a strong candidate for a disease-causing variant, however, the possibility it may be a rare benign variant cannot be excluded.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004300120.1

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

Description

This sequence change affects codon 213 of the PGK1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PGK1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with phosphoglycerate kinase 1 deficiency (PMID: 30111548). ClinVar contains an entry for this variant (Variation ID: 167466). Studies have shown that this variant is associated with altered splicing resulting in reduced mRNA expression (PMID: 17661373). For these reasons, this variant has been 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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000203250	Eurofins Ntd Llc (ga)	flagged submission Reason: Older claim that does not account for recent evidence Notes: None (EGL Classification Definitions 2015)	Uncertain significance (Dec 20, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000203250

Eurofins Ntd Llc (ga)

flagged submission

Reason: Older claim that does not account for recent evidence

Notes: None

(EGL Classification Definitions 2015)

Uncertain significance
(Dec 20, 2013)

germline

clinical testing

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

Citation Link

Last Updated: Nov 30, 2024

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