rs766074609

chr17-80108398-T-Cchr17-80108398-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1064T>C(p.Leu355Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L355L) has been classified as Likely benign.

• 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:10
• Conservation: PhyloP100: 1.71

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-80108398-T-C is Pathogenic according to our data. Variant chr17-80108398-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 284093.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80108398-T-C is described in Lovd as [Pathogenic]. Variant chr17-80108398-T-C is described in Lovd as [Likely_pathogenic]. Variant chr17-80108398-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1064T>C	p.Leu355Pro	missense_variant	6/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1064T>C	p.Leu355Pro	missense_variant	6/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250882 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135824

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1064T>C;p.(Leu355Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 284093; PMID: 14695532; 14972326; 24016645; 23787031; 23632174; 23430493) -.PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 14972326) - PS3_supporting. The variant is present at low allele frequencies population databases (rs766074609– gnomAD 0.00007972%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu355Pro) was detected in trans with a pathogenic variant (PMID: 14695532; 14972326; 24016645; 23787031; 23632174; 23430493) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2021	Variant summary: GAA c.1064T>C (p.Leu355Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250882 control chromosomes (gnomAD). c.1064T>C has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Pittis_2008, Nino_2012). One of these publications also reported experimental evidence evaluating an impact on protein function, and found the complete absence of enzyme activity and lack protein product in transiently transfected COS cells (Hermans_2004). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters, including one expert panel (ClinGen), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Leu355Pro variant in GAA has been reported in 23 individuals (including 4 Italian, 4 Portuguese, 2 Israeli, 2 Columbian, 1 German, 1 Turkish, and 1 Syrian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 16917947, 14972326, 18429042, 17643989, 14695532, 17723315, 23632174, 23430493, 23787031, 24016645, 30023291, 17213836, 17573812, 30595407), and has also been reported pathogenic by Counsyl and EGL in ClinVar (Variation ID: 284093). This variant has been identified in 0.003% (1/34580) of Latino chromosomes and 0.001% (1/113290) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766074609). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Leu355Pro variant may impact GAA processing and activity (PMID: 14695532, 14972326). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Leucine (Leu) at position 355 is not conserved in one mammal species and more evolutionary distant species, slightly raising the possibility that a change at this position may be tolerated. The presence of this variant in the homozygous state and in combination with pathogenic and likely variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Leu355Pro variant is pathogenic (PMID: 23430493, 24016645, 23632174, 17723315, 14972326). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 23430493, 24016645, 23632174, 17723315, 14972326). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant and multiple occurrences with pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP3, PP4 (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 07, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 355 of the GAA protein (p.Leu355Pro). This variant is present in population databases (rs766074609, gnomAD 0.003%). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 14972326, 18429042, 23430493, 23632174). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 14972326). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 29, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2020	- -

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.81
Sift	Benign	0.087	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.99	D;D
Vest4		0.95
MutPred		0.90		Loss of stability (P = 0.013);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs766074609; hg19: chr17-78082197;