rs766074609

Variant names:

• chr17-80108398-T-C
• rs766074609
• NM_000152.5:c.1064T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-80108398-T-C
• chr17-80108398-T-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS3_Moderate PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1064T>C variant in GAA is a missense variant predicted to cause substitution of leucine to proline at amino acid 355 (p.Leu355Pro). This variant has been reported in over 20 individuals with Pompe disease including at least 9 individuals with documented laboratory values showing GAA deficiency (PP4_Moderate) (PMIDs 14972326, 17213836, 17723315, 17213836, 23632174, 24016645, 30595407)(PP4_Moderate). The variant is homozygous in multiple patients (PMIDs 14972326, 16917947, 17213836, 17573812, 17723315, 18429042, 22658377, 23787031, 24016645, 30023291, 33325062). Three individuals are compound heterozygous for the variant and another variant that has been assessed as pathogenic by the ClinGen LSD VCEP; c.-32-13T>G in two patients (PMIDs 17643989, 21803581), and confirmed in trans with c.670C>T (p.Arg224Trp) in another patient (PMID 23632174; (PM3_Strong). p.Leu355Pro has also been reported in individuals with Pompe disease who are compound heterozygous for c.2041-2A>C (PMID 33325062), c.2303C>G (p.Pro768Arg) (PMID 17027861), c.1210G>A (p.Asp404Asn) (PMID 22658377, 23787031), c.1120T>C (p.Cys374Arg) (PMID 14695532), c.1927G>A (p.Gly643Arg) (PMID 18429042), c.1106T >C (p.Leu369Pro) (PMID 23430493), and c.380G>T (p.Cys127Phe) (PMID 24016645). The in trans data from these patients will be used in the assessment of the other variant and was not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34580) in the Latino population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in absent GAA activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 284093, 2 star review status) with four submitters each classifying the variant as pathogenic. 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): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815136/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 1.71
• Publications: 26 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.

• PS3: 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.
• PP3: 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.1064T>C	p.Leu355Pro	missense	Exon 6 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1064T>C	p.Leu355Pro	missense	Exon 7 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1064T>C	p.Leu355Pro	missense	Exon 6 of 20	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.1064T>C	p.Leu355Pro	missense	Exon 6 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1064T>C	p.Leu355Pro	missense	Exon 7 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1064T>C	p.Leu355Pro	missense	Exon 6 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250882 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461082 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000409 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Glycogen storage disease, type II (10)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.81
Sift	Benign	0.087	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.95
MutPred		0.90		Loss of stability (P = 0.013)
MVP		0.99
MPC		0.57
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.95
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs766074609; hg19: chr17-78082197;