rs1055945806

Variant names:

• chr17-80104552-C-A
• rs1055945806
• NM_000152.5:c.-32-3C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80104552-C-A
• chr17-80104552-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PS1_Supporting PVS1_Strong PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.-32-3C>A variant is located in the splice acceptor region of intron 1 and has been shown to impact splicing. In fibroblasts from an individual with Pompe disease who was compound heterozygous for the variant and a missense variant in GAA, RT-PCR revealed loss of exon 2 (p.M1_T182del, which includes the 27 residues of signal sequence, the 42 residues of the propeptide and the first 113 amino acids of the mature protein (from 70 to 182) (PMID:18429042). A later study, in which the variant was expressed in a minigene, showed that the variant results in about 20% of transcripts with normal splicing of exon 2 (of note, this is a slightly lower level of normal splicing than observed for a well known pathogenic variant in the same splice region, c.-32-13T>G). Abnormal splicing events included complete loss of exon 2 (r.-32_546del) and activation of a cryptic splice site (r.‐32_486del) (PMID:31301153). Due to loss of a critical region (the signal sequence) in aberrantly spliced transcripts, but with presence of some normal transcript (albeit at a lower level than a known pathogenic variant in the same splice region), PVS1 was applied at the strong level (PMID:37352859) (PVS1_Strong, PS1_Supporting applied based on recommendations in PMID:37352859). This variant has been reported in at least 6 probands with late onset Pompe disease including two individuals with documented GAA activity <30% normal in fibroblasts (PMID:19046416, 21550241) (PP4_Moderate). Two of these probands have been reported to have this variant in compound heterozygosity, phase unknown, with another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.1655T>C (p.Leu552Pro) (PMID:18429042) and c.482_483del (PMID:21550241). In addition, three affected siblings have been reported to be homozygous for the variant (PMID:19588081, 20464284, 25681614) (PM3). Another three patients are compound heterozygous for the variant and a missense variant (either c.1905C>A (p.Asn635Lys), c.1447G>A (p.Gly483Arg), or c.2173C>T (p.Arg725Trp)) (PMID:19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.0. is 0.000007314 (8/1093866 alleles) in the European non-Finnish populationn, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371662). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1_Strong, PM3, PS1_Supporting, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041878/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, intron
• Scores: Splicing: ADA: 0.4710
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 0.341
• 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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.-32-3C>A		splice_region intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.-32-3C>A		splice_region intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.-32-3C>A		splice_region intron	N/A	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.-32-3C>A		splice_region intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.-32-3C>A		splice_region intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000945488.1		c.-35C>A		5_prime_UTR	Exon 2 of 20	ENSP00000615547.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000559 AC: 8 AN: 1430012 Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3 AN XY: 707696

African (AFR) AF: 0.00 AC: 0 AN: 32950

American (AMR) AF: 0.00 AC: 0 AN: 42954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39228

South Asian (SAS) AF: 0.00 AC: 0 AN: 84058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5136

European-Non Finnish (NFE) AF: 0.00000731 AC: 8 AN: 1093866

Other (OTH) AF: 0.00 AC: 0 AN: 58942

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Glycogen storage disease, type II (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.34
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.19		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: rs1055945806; hg19: chr17-78078351;