rs797044505

Variant names:

• chrX-78118168-C-T
• rs797044505
• NM_000291.4:c.639C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000291.4(PGK1):​c.639C>T​(p.Gly213Gly) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PGK1 NM_000291.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.2133
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.74
• Publications: 3 publications found

Genes affected

PGK1 (HGNC:8896): (phosphoglycerate kinase 1) The protein encoded by this gene is a glycolytic enzyme that catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. The encoded protein may also act as a cofactor for polymerase alpha. Additionally, this protein is secreted by tumor cells where it participates in angiogenesis by functioning to reduce disulfide bonds in the serine protease, plasmin, which consequently leads to the release of the tumor blood vessel inhibitor angiostatin. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Deficiency of the enzyme is associated with a wide range of clinical phenotypes hemolytic anemia and neurological impairment. Pseudogenes of this gene have been defined on chromosomes 19, 21 and the X chromosome. [provided by RefSeq, Jan 2014]

PGK1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to phosphoglycerate kinase 1 deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant X-78118168-C-T is Pathogenic according to our data. Variant chrX-78118168-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167466.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000291.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGK1	NM_000291.4	MANE Select	c.639C>T	p.Gly213Gly	splice_region synonymous	Exon 6 of 11	NP_000282.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGK1	ENST00000373316.5	TSL:1 MANE Select	c.639C>T	p.Gly213Gly	splice_region synonymous	Exon 6 of 11	ENSP00000362413.4
	PGK1	ENST00000644362.1		c.555C>T	p.Gly185Gly	splice_region synonymous	Exon 6 of 11	ENSP00000496140.1
	PGK1	ENST00000491291.1	TSL:5	n.631C>T		splice_region non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 07, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 20, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glycogen storage disease due to phosphoglycerate kinase 1 deficiency Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phosphoglycerate kinase 1 deficiency (MIM#300653). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, pathogenic, and as a VUS in ClinVar. Additionally, it has been observed as hemizygous in two brothers with exercise induced muscle stiffness and myoglobinuria, and as heterozygous in their mildly affected sister (PMIDs: 17661373, 10809925). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Quantitative PCR on blood samples from individuals heterozygous or hemizygous for this variant has shown that it results in a reduction of PGK1 mRNA expression (PMID: 17661373). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.56
PhyloP100		3.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=87/13	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.21
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -2
DS_DL_spliceai		0.49		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044505; hg19: chrX-77373665; COSMIC: COSV64832752; COSMIC: COSV64832752;