rs1555601802

chr17-80113333-CG-Cchr17-80113333-CG-CGG

Variant summary

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

The NM_000152.5(GAA):c.2161del(p.Glu721ArgfsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,441,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A719A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: -4.27

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80113333-CG-C is Pathogenic according to our data. Variant chr17-80113333-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 932900.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2161del	p.Glu721ArgfsTer43	frameshift_variant	15/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2161del	p.Glu721ArgfsTer43	frameshift_variant	15/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1441992 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 715150

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Apr 20, 2020

This variant, c.2161del (p.Glu721ArgfsTer?), is a frameshift variant predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was identified by a clinical diagnostic laboratory in a compound heterozygous individual with c.841C>T (p.Arg281Trp). Pseudodeficiency variants are absent in this individual, allowing PP4_Moderate to be applied. The in trans data from this patient was used in the classification of p.Arg281Trp and is not included here in order to avoid a circular argument. An additional case has been reported with p.Glu721ArgfsTer (cDNA sequence not provided), identified by newborn screening and compound heterozygous for p.Trp746Leu and the psuedodeficiency variant p.Asp91Asn (PMIDs 28196920, 29095812). There is no ClinVar entry for this variant and, to our knowledge, functional studies are unavailable. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4_Moderate. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555601802; hg19: chr17-78087132;