17-80108495-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1082C>T(p.Pro361Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,962 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P361R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 7.39

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80108495-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289367.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-80108495-C-T is Pathogenic according to our data. Variant chr17-80108495-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 403712.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80108495-C-T is described in Lovd as [Pathogenic]. Variant chr17-80108495-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-80108495-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1082C>T	p.Pro361Leu	missense_variant	7/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1082C>T	p.Pro361Leu	missense_variant	7/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249370 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460752 Hom.: 0 Cov.: 38 AF XY: 0.00000550 AC XY: 4 AN XY: 726714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000260 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Pro361Leu variant in GAA has been reported in at least 15 individuals (including 6 Chinese, 2 Italian, and 1 from the UK) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 30023291, 27692865, 26497565, 25526786, 25213570, 25139343, 21484825, 16917947, 12601120, 24169249, 26685070, 17915575), and has also been reported pathogenic by Claritas Genomics and Invitae in ClinVar (Variation ID: 403712). This variant has been identified in 0.006% (2/34496) of Latino chromosomes and 0.005% (1/21462) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755253527). 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 a minigene assay and COS cells transfected with the variant provide some evidence that the p.Pro361Leu variant may eliminate proteolytically activated GAA and impact GAA activity (PMID: 22644586, 12601120). 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. This variant was reported in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II (PMID: 21484825, 12601120, 26497565, 16917947, 26685070, 30023291, 27692865, 25213570, 25139343). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue (PMID: 21484825, 26497565, 25139343, 12601120). One additional variant at the same position, p.Pro361Arg, has been reported as a VUS in ClinVar (Variation ID: 289367). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Oct 06, 2016	The c.1082C>T (p.Pro361Leu) missense variant is previously reported in the literature and is expected to be causative of disease. This variant has been reported in multiple affected individuals across multiple studies. This variant is classified as Class B, which means potentially less severe (Kroos M et al. Hum Mutat. 2012;33(8):1161-5). Patients with this class of variant are CRIM-positive. This variant involves a highly conserved nucleotide and amino acid. PolyPhen-2, SIFT, and MutationTaster all predict this variant to be deleterious. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 361 of the GAA protein (p.Pro361Leu). This variant is present in population databases (rs755253527, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 12601120, 16917947, 25213570, 27344650, 30023291). 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: 403712). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 12601120). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2022	Variant summary: GAA c.1082C>T (p.Pro361Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249370 control chromosomes. c.1082C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 16, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jun 03, 2022	The NM_000152.5:c.1082C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 361 (p.Pro361Leu). This variant has been reported in at least 13 individuals with clinical symptoms consistent with Pompe disease including 6 individuals with documented laboratory values showing deficiency of GAA activity below normal range in leukocytes or <1% activity in fibroblasts or another tissue, many of whom were also reported to be showing improvement on enzyme replacement therapy and/or had specific features reported for infantile onset Pompe disease including cardiomyopathy and motor delay (PMID: 21484825, 25139343, 25526786, 26497565, 27344650, 31439017, 31915562) and another patient with features specific for infantile onset Pompe disease, on enzyme replacement therapy (PMID: 30023291). Pseudodeficiency variants, c.1726G>A and c.2065G>A, were reported to be absent in at least one of these patients (PMID: 25526786) (PP4_Moderate). Of the patients reported with this variant, four are compound heterozygous for the variant and another variant in GAA classified as pathogenic by the ClinGen LSD VCEP including c.784G>A (p.Glu262Lys) (PMID: 31915562; confirmed in trans by parental DNA testing) and c.1933G>A (p.Asp645Asn) (PMID: 26497565, 27344650; phase unknown), c.1935C>A (p.Asp645Glu) (PMID: 31439017; phase unknown), and c.2238G>C (p.Trp746Cys) (PMID: 35123860; phase unknown). In addition, two homozygotes have been reported (PMID: 30023291, 31931849), one of whom was identified by next generation sequencing panel for limb girdle muscle weakness, and not counted due to no report of follow up enzyme studies to confirm diagnosis of Pompe disease (PMID: 31931849) (PM3_Strong). Additional patients have been reported with the variant in compound heterozygosity with another variant including c.503G>C (p.Arg168Pro) (PMID: 25526786), c.953T>C (p.Met318Thr) (PMID: 25139343), c.1309C>T (p.Arg437Cys) (PMID: 12601120, 27692865), c.1432G>A (p.Gly478Arg) (PMID: 25213570), c.1979G>A (p.Arg660His) (PMID: 21484825), and c.1551+1G>C (PMID: 16917947). In these cases, the allelic data will be used in the assessment of the second variant and was not applied to PM3 here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells and GAA deficient fibroblasts, this variant resulted in <4% wild type GAA activity in three different studies (PMID: 12601120, 19862843, 22644586) and showed evidence of abnormal synthesis and processing on Western blot (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at the same codon, c.1082C>A (p.Pro361Arg) has been reported (PMID: 31076647). The classification of p.Pro163Leu will be used in the assessment of p.Pro361Arg and, therefore, PM5 is not applied here. There is a ClinVar entry for this variant (Variation ID: 403712, 2 star review status) with four submitters classifying the variant as pathogenic and two as likely 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: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	Published functional studies demonstrate a damaging effect with significantly reduced enzymatic activity compared to wildtype (Kroos et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28592009, 30281819, 25213570, 12601120, 16917947, 27344650, 30275481, 30023291, 34134972, 31086307, 22644586, 34539730, 31915562) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-9.3	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.90		Gain of catalytic residue at P361 (P = 0.0183);Gain of catalytic residue at P361 (P = 0.0183);
MVP		0.97
MPC		0.55
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.94

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: rs755253527; hg19: chr17-78082294;