rs786204517

Positions:

• chr17-80108569-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: This variant, c.1156C>T (p.Gln386Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. This variant is absent in gnomAD v2.1.1, meeting PM3. A Korean patient with infantile onset Pompe disease, meeting the specifications for PP4, has been reported. This patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg). This in trans data has been used in the assessment of p.Ser619Arg and was not be included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 188858; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274049/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 0.213

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 11 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1156C>T	p.Gln386*	stop_gained	7/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1156C>T	p.Gln386*	stop_gained	7/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 30, 2014	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 06, 2020	This variant, c.1156C>T (p.Gln386Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. This variant is absent in gnomAD v2.1.1, meeting PM3. A Korean patient with infantile onset Pompe disease, meeting the specifications for PP4, has been reported. This patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg). This in trans data has been used in the assessment of p.Ser619Arg and was not be included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 188858; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.74	D
Vest4		0.85
GERP RS		3.3

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: rs786204517; hg19: chr17-78082368;