7-44065297-C-T

Variant names:

• chr7-44065297-C-T
• rs10250779
• NM_000290.4:c.233G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 16P and 2B. PVS1 PP5_Very_Strong BS1_Supporting BS2_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.68
• Publications: 15 publications found

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]

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]

ENSG00000239775 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 130 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000290.4. 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
	PGAM2	NM_000290.4	MANE Select	c.233G>A	p.Trp78*	stop_gained	Exon 1 of 3	NP_000281.2
	DBNL	NM_001014436.3	MANE Select	c.*4381C>T		3_prime_UTR	Exon 13 of 13	NP_001014436.1
	DBNL	NM_001122956.2		c.*4381C>T		3_prime_UTR	Exon 13 of 13	NP_001116428.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAM2	ENST00000297283.4	TSL:1 MANE Select	c.233G>A	p.Trp78*	stop_gained	Exon 1 of 3	ENSP00000297283.3
	DBNL	ENST00000448521.6	TSL:1 MANE Select	c.*4381C>T		3_prime_UTR	Exon 13 of 13	ENSP00000411701.1
	ENSG00000239775	ENST00000425727.1	TSL:5	n.293C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152216 Hom.: 2 Cov.: 33

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

GnomAD2 exomes AF: 0.000530 AC: 133 AN: 251076 AF XY: 0.000420

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 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.: 3 Cov.: 35 AF XY: 0.000179 AC XY: 130 AN XY: 727020

African (AFR) AF: 0.00836 AC: 280 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.000480 AC: 29 AN: 60390

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152334 Hom.: 2 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74490

African (AFR) AF: 0.00681 AC: 283 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000445 Hom.: 1

Bravo AF: 0.00237

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type X Pathogenic:7

Jan 28, 2025

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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.

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.

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

not provided Pathogenic:3

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

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)

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.7
Vest4		0.27
GERP RS		5.9
PromoterAI		0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=17/183	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs10250779; hg19: chr7-44104896;