rs786204621

Positions:

• chr17-80113007-CACA-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000152.5(GAA):​c.2024_2026del​(p.Asn675del) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.19

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity LYAG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 17-80113007-CACA-C is Pathogenic according to our data. Variant chr17-80113007-CACA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80113007-CACA-C is described in Lovd as [Pathogenic]. Variant chr17-80113007-CACA-C is described in Lovd as [Likely_pathogenic]. Variant chr17-80113007-CACA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2024_2026del	p.Asn675del	inframe_deletion	14/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2024_2026del	p.Asn675del	inframe_deletion	14/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000828 AC: 2 AN: 241688 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	Experimental studies have shown that this variant affects GAA function (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 189006). This variant has been observed in individuals with Pompe disease (PMID: 9554747, 10338092, 29046207). This variant is present in population databases (rs773958269, gnomAD 0.01%). This variant, c.2024_2026del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Asn675del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	Variant summary: GAA c.2024_2026delACA (p.Asn675del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 8.3e-06 in 241688 control chromosomes (i.e., 2 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2024_2026delACA has been reported in the literature in multiple compound heterozygousindividuals affected with infantile-onset Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g., Shieh_1998, Fu_2014, Chen_2017, Ngiwsara_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28394184, 24269976, 31510962, 9554747). Two 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs786204621; hg19: chr17-78086806;