rs1555598888

Variant names:

• chr17-80105042-GACCCGT-G
• rs1555598888
• NM_000152.5:c.460_465delCGTACC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000152.5(GAA):​c.460_465delCGTACC​(p.Arg154_Thr155del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R154R) has been classified as Likely benign. The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 5.54
• Publications: 2 publications found

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000152.5.
• PP5: Variant 17-80105042-GACCCGT-G is Pathogenic according to our data. Variant chr17-80105042-GACCCGT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551306.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.460_465delCGTACC	p.Arg154_Thr155del	conservative_inframe_deletion	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.460_465delCGTACC	p.Arg154_Thr155del	conservative_inframe_deletion	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.460_465delCGTACC	p.Arg154_Thr155del	conservative_inframe_deletion	Exon 2 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.460_465delCGTACC	p.Arg154_Thr155del	conservative_inframe_deletion	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.460_465delCGTACC	p.Arg154_Thr155del	conservative_inframe_deletion	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.460_465delCGTACC	p.Arg154_Thr155del	conservative_inframe_deletion	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	2	-	Glycogen storage disease, type II (5)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5

Splicing

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

Other links and lift over

dbSNP: rs1555598888; hg19: chr17-78078841;