rs1555600235

Positions:

• chr17-80108816-CATG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4_Supporting PP5_Strong

The NM_000152.5(GAA):​c.1320_1322del​(p.Met440del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 7.49

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000152.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-80108816-CATG-C is Pathogenic according to our data. Variant chr17-80108816-CATG-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 526518.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr17-80108816-CATG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1320_1322del	p.Met440del	inframe_deletion	8/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1320_1322del	p.Met440del	inframe_deletion	8/20	1	NM_000152.5	P1

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

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:1 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 03, 2022	The NM_000152.5:c.1317delGAT or c.1320_1322delGAT variant is predicted to cause a change in the length of protein due to inframe deletion of one amino acid, Met440 in a non repeat region (PM4_Supporting). This variant is documented in NBS-Pompe program from Japan (PMID: 31076647). One LOPD patient from China was reported to be compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.2238G>C (p.Trp746Cys)(PM3_supporting). This patient had documented deficiency of GAA activity (PMID: 35071497) (PP4_moderate). The variant is absent in gnomAD v2.1.1 (PM2_supporting). The results of in silico predictors were conflicting. To our knowledge, no functional studies have been performed on this variant. There is a ClinVar entry for this variant (Variant ID: 526518). Due to insufficient evidence this variant is classified as of uncertain significance for Pompe disease based on ACMG/AMP criteria applied, as specified by LSD VCEP (specification version 2.0). Criteria applied: criteria: PM2_supporting; PM3_supporting, PM4_Supporting, PP4_moderate. (Classification approved by the ClinGen LSD VCEP on Nov 3, 2022). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 01, 2019	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with Pompe disease (PMID: 25526786, 28394184, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1315_1317delATG in the literature. ClinVar contains an entry for this variant (Variation ID: 526518). This variant is not present in population databases (ExAC no frequency). This variant, c.1320_1322del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Met440del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555600235; hg19: chr17-78082615;