chr1-63593574-TCC-T

Variant names:

• chr1-63593574-TCC-T
• rs1570463842
• NM_002633.3:c.87_88delCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002633.3(PGM1):​c.87_88delCC​(p.Phe29LeufsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PGM1 NM_002633.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.46

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]

ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-63593574-TCC-T is Pathogenic according to our data. Variant chr1-63593574-TCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 663105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGM1	NM_002633.3	c.87_88delCC	p.Phe29LeufsTer75	frameshift_variant	Exon 1 of 11	ENST00000371084.8	NP_002624.2
PGM1	NM_001172819.2	c.-915_-914delCC		upstream_gene_variant			NP_001166290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGM1	ENST00000371084.8	c.87_88delCC	p.Phe29LeufsTer75	frameshift_variant	Exon 1 of 11	1	NM_002633.3	ENSP00000360125.3
PGM1	ENST00000650546.1	c.87_88delCC	p.Phe29LeufsTer75	frameshift_variant	Exon 1 of 12			ENSP00000497812.1
ITGB3BP	ENST00000478138.1	n.146_147delGG		non_coding_transcript_exon_variant	Exon 1 of 5	3
PGM1	ENST00000540265.5	c.-915_-914delCC		upstream_gene_variant		2		ENSP00000443449.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461482 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PGM1-congenital disorder of glycosylation Pathogenic:4

Dec 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: PGM1 c.87_88delCC (p.Phe29LeufsX75) 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 was absent in 249576 control chromosomes. c.87_88delCC has been reported in the literature in at least one compound heterozygous individual affected with PGM1 deficiency (e.g. Conte_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33342467). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 27, 2024

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.Phe29Leufs*75) in the PGM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGM1 are known to be pathogenic (PMID: 22492991). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PGM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 663105). For these reasons, this variant has been classified as Pathogenic. -

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Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 20, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1570463842; hg19: chr1-64059245;