7-44065297-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting

The NM_000290.4(PGAM2):c.233G>A(p.Trp78*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,613,696 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

PGAM2
NM_000290.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.68

Variant links:

Genes affected

PGAM2 (HGNC:8889): (phosphoglycerate mutase 2) Phosphoglycerate mutase (PGAM) catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. The PGAM is a dimeric enzyme containing, in different tissues, different proportions of a slow-migrating muscle (MM) isozyme, a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM subunit. Mutations in this gene cause muscle phosphoglycerate mutase eficiency, also known as glycogen storage disease X. [provided by RefSeq, Sep 2009]

PGAM2 links:

DBNL (HGNC:2696): (drebrin like) Enables cadherin binding activity. Predicted to be involved in several processes, including Rac protein signal transduction; nervous system development; and podosome assembly. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DBNL links:

ENSG00000239775 (HGNC:):

ENSG00000239775 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-44065297-C-T is Pathogenic according to our data. Variant chr7-44065297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000222 (325/1461362) while in subpopulation AFR AF= 0.00836 (280/33478). AF 95% confidence interval is 0.00756. There are 3 homozygotes in gnomad4_exome. There are 130 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM2	NM_000290.4 link	c.233G>A	p.Trp78*	stop_gained	Exon 1 of 3	ENST00000297283.4	NP_000281.2	P15259
DBNL	NM_001014436.3 link	c.*4381C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000448521.6	NP_001014436.1	Q9UJU6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM2	ENST00000297283.4 link	c.233G>A	p.Trp78*	stop_gained	Exon 1 of 3	1	NM_000290.4	ENSP00000297283.3		P15259
DBNL	ENST00000448521.6 link	c.*4381C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_001014436.3	ENSP00000411701.1		Q9UJU6-1

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

293

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00683

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000530

AC:

133

AN:

251076

Hom.:

AF XY:

0.000420

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00738

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000222

AC:

325

AN:

1461362

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.00836

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152334

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00681

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000312

Hom.:

Bravo

AF:

0.00237

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000733

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type X

Pathogenic:7

Mar 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233G>A;p.(Trp78*) variant creates a premature translational stop signal in the PGAM2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 418; PMID: 10545043; 16881065; 18852891; 19783439; 21444020; 23169535; 27612597) - PS4. The p.(Trp78*) was detected in trans with a pathogenic variant (PMID: 10545043; 16881065; 19783439; 27612597) - PM3_strong and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -

Sep 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PGAM2 c.233G>A (p.Trp78X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00053 in 251076 control chromosomes in the gnomAD database, including 1 homozygotes c.233G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type X (e.g. Tsujino_1993). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_000290.3:c.233G>A in the PGAM2 gene has an allele frequency of 0.007 in African subpopulation in the gnomAD database. Koo B et al. found compound heterozygous variants: c.233G>A, and c.278G>A in a patient with Phosphoglycerate mutase deficiency (PMID: 27612597). In addition, Tsujino S et al. found that three patients with phosphoglycerate mutase (PGAM) deficiency were homozygous for this nonsense variant (PMID: 8447317 ). The c.233G>A (p.Trp78*) variant in the PGAM2 gene results in a premature termination codon, predicted to cause a truncated or absent protein due to nonsense mediated decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp78*) in the PGAM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGAM2 are known to be pathogenic (PMID: 8447317, 19273759). This variant is present in population databases (rs10250779, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with phosphoglycerate mutase deficiency (PMID: 8447317, 27612597). ClinVar contains an entry for this variant (Variation ID: 418). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Jan 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The most common pathogenic variant identified in patients of African ancestry with PGAM deficiency, likely due to a founder effect (Koo et al., 2016); 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; This variant is associated with the following publications: (PMID: 8447317, 23169535, 27612597, 28944235, 19783439, 28492532, 6308514, 2987758, 31589614, 27535533) -

Feb 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PS4_moderate, PVS1 -

Dec 29, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PGAM2-related disorder

Pathogenic:1

Nov 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PGAM2 c.233G>A variant is predicted to result in premature protein termination (p.Trp78*). This is the most commonly reported causative variant in patients with phosphoglycerate mutase enzyme deficiency (Tsujino et al. 1993. PubMed ID: 8447317; Salameh et al. 2013. PubMed ID: 23169535; Koo and Oskarsson. 2016. PubMed ID: 27612597). This variant has been reported primarily in patients of African descent, which is consistent with the relatively high minor allele frequency in this population in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

Vest4

0.27

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over