rs1553121290

Variant names:

• chr1-63636374-T-A
• rs1553121290
• NM_002633.3:c.1014T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002633.3(PGM1):​c.1014T>A​(p.Ser338Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGM1 NM_002633.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.719
• Publications: 1 publications found

Genes affected

PGM1 (HGNC:8905): (phosphoglucomutase 1) The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause glycogen storage disease type 14. Alternativley spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Mar 2010]

PGM1 Gene-Disease associations (from GenCC):

• PGM1-congenital disorder of glycosylation

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 1-63636374-T-A is Pathogenic according to our data. Variant chr1-63636374-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471070.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGM1	NM_002633.3	c.1014T>A	p.Ser338Arg	missense_variant	Exon 6 of 11	ENST00000371084.8	NP_002624.2
PGM1	NM_001172818.1	c.1068T>A	p.Ser356Arg	missense_variant	Exon 6 of 11		NP_001166289.1
PGM1	NM_001172819.2	c.423T>A	p.Ser141Arg	missense_variant	Exon 6 of 11		NP_001166290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGM1	ENST00000371084.8	c.1014T>A	p.Ser338Arg	missense_variant	Exon 6 of 11	1	NM_002633.3	ENSP00000360125.3
PGM1	ENST00000650546.1	c.1014T>A	p.Ser338Arg	missense_variant	Exon 6 of 12			ENSP00000497812.1
PGM1	ENST00000371083.4	c.1068T>A	p.Ser356Arg	missense_variant	Exon 6 of 11	2		ENSP00000360124.4
PGM1	ENST00000540265.5	c.423T>A	p.Ser141Arg	missense_variant	Exon 6 of 11	2		ENSP00000443449.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Apr 02, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30982613, 31307013, 33342467) -

PGM1-congenital disorder of glycosylation Uncertain:1

May 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 471070). This missense change has been observed in individual(s) with clinical features of PGM1-congenital disorder of glycosylation (PMID: 33342467; Invitae). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 338 of the PGM1 protein (p.Ser338Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.43	N
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Uncertain	2.9	M;.;.;.
PhyloP100		-0.72
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.3	D;.;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.83		Gain of methylation at S338 (P = 0.0204);Gain of methylation at S338 (P = 0.0204);.;.;
MVP		0.82
MPC		0.75
ClinPred		0.99	D
GERP RS		-2.6
Varity_R		0.95
gMVP		0.98
Mutation Taster		=26/74	disease causing

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: rs1553121290; hg19: chr1-64102045;