17-80108305-C-T

Position:

chr17-80108305-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.971C>T variant in GAA is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 324 (p.Pro324Leu). One patient is reported to be compound heterozygous for the variant and c.794G>A (p.Ser265Asn). However the clinical symptoms were not consistent with Pompe disease. Another patient, with history of muscle weakness, had documented GAA deficiency in leukocytes after immunoprecipitation, 15% of normal mean control level, which does not meet the LD VCEP's threshold for PP4. IN addition, the cDNA changes for the variants in this patient was not provided, and therefore this data was not included (PMID:11071489) (PP4 not met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004014 (1/24914 alleles) in the African /African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.788 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3). When expressed in CHO cells, the variant has activity >2% normal but, because further details are not available regarding the activity of the variant, PS3 was not applied. There is a ClinVar entry for this variant (Variant ID: 431990). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease, based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications version 2.0): PM2_Supporting, PP3.(The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Oct. 4th, 2022. The classification was re-evaluated and re-approved on April 2, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815119/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:5

Conservation

PhyloP100: 4.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

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 linkuse as main transcript	c.971C>T	p.Pro324Leu	missense_variant	6/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.971C>T	p.Pro324Leu	missense_variant	6/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251214

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:4Uncertain:5

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 02, 2024	The NM_000152.5:c.971C>T variant in GAA is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 324 (p.Pro324Leu). One patient is reported to be compound heterozygous for the variant and c.794G>A (p.Ser265Asn). However the clinical symptoms were not consistent with Pompe disease. Another patient, with history of muscle weakness, had documented GAA deficiency in leukocytes after immunoprecipitation, 15% of normal mean control level, which does not meet the LD VCEP's threshold for PP4. IN addition, the cDNA changes for the variants in this patient was not provided, and therefore this data was not included (PMID:11071489) (PP4 not met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004014 (1/24914 alleles) in the African /African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.788 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3). When expressed in CHO cells, the variant has activity >2% normal but, because further details are not available regarding the activity of the variant, PS3 was not applied. There is a ClinVar entry for this variant (Variant ID: 431990). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease, based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications version 2.0): PM2_Supporting, PP3. (The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Oct. 4th, 2022. The classification was re-evaluated and re-approved on April 2, 2024). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2017	Variant summary: The GAA c.971C>T (p.Pro324Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/246128 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant was reported in a patient with severe infantile form of Pompe disease who carried a second second GAA mutation (W490X) and had 15% residual GAA activity (Laforet_2000). Additionally, a functional study performed in COS-7 cells showed the variant to have reduced GAA activity and GAA protein compared to wild-type (Flanagan_2009). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Pro324Leu variant in GAA has been reported in 1 French individual with Glycogen Storage Disease II (PMID: 11071489), and has also been reported as a likely pathogenic variant by GeneDx and Integrated Genetics, and a VUS by Counsyl in ClinVar (Variation ID: 431990). This variant has been identified in 0.004% (1/24914) of African chromosomes, 0.003% (1/30616) of South Asian chromosomes and 0.0007754% (1/128970) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750030887). 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.Pro324Leu variant may impact GAA processing based on Western Blots (PMID: 19862843). 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 a rare nonsense variant and in an individual with Glycogen Storage Disease II (PMID: 11071489). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 324 of the GAA protein (p.Pro324Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of GAA-related conditions (PMID: 11071489, 34864681). ClinVar contains an entry for this variant (Variation ID: 431990). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GAA function (PMID: 19862843). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	Functional studies found that P324L is associated with reduced acid alpha-glucosidase compared to wild-type (Flanagan et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11071489, 19862843) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

4.0

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-9.3

D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.77

MutPred

0.77

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

1.0

MPC

0.54

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over