rs121907940

Variant names:

• chr17-80107837-T-C
• rs121907940
• NM_000152.5:c.896T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-80107837-T-C
• chr17-80107837-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_Moderate PS3 PM3 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.896T>C variant in GAA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 299 (p.Leu299Pro). At least 4 individuals have been reported with this variant and either diagnosis of Pompe disease with ERT treatment or GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/unknown tissue (PMIDs 26622091, 26873529, 25626711,29422078). Another patient was homozygous for this variant and identified by newborn screening for Pompe disease (PMID:22133539). This meets the criteria for PP4_Moderate. This variant has been detected in at least 7 individuals with Pompe disease or identified by newborn screening for Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G (PMID:18757064, 26622091, 26873529). At least 1 individual was homozygous for the variant (PMID:22133539,25626711). Criteria for PM3 were met. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal synthesis and processing on Western blots leading the variant to be described as Class B (“potentially less severe”, indicating that this variant may impact protein function (PMID:18425781)(PS3). REVEL Score = 0.952 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 180144, 2 star review status) with 5 submitters classifying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PS3, PP4_Moderate, PM3, PM2_Supporting, PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA273686/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.85

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.896T>C	p.Leu299Pro	missense_variant	Exon 5 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.896T>C	p.Leu299Pro	missense_variant	Exon 5 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459968 Hom.: 0 Cov.: 56 AF XY: 0.00000275 AC XY: 2 AN XY: 726262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

-

Medical Genetic Department, Shiraz University Of Medical Science

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu299 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7717400; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GAA function (PMID: 18425781). 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. ClinVar contains an entry for this variant (Variation ID: 180144). This missense change has been observed in individuals with clinical features of Pompe disease (PMID: 25752415, 29422078). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 299 of the GAA protein (p.Leu299Pro). -

May 11, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.896T>C variant in GAA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 299 (p.Leu299Pro). At least 4 individuals have been reported with this variant and either diagnosis of Pompe disease with ERT treatment or GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/unknown tissue (PMIDs 26622091, 26873529, 25626711,29422078). Another patient was homozygous for this variant and identified by newborn screening for Pompe disease (PMID: 22133539). This meets the criteria for PP4_Moderate. This variant has been detected in at least 7 individuals with Pompe disease or identified by newborn screening for Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G (PMID:18757064, 26622091, 26873529). At least 1 individual was homozygous for the variant (PMID: 22133539,25626711). Criteria for PM3 were met. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal synthesis and processing on Western blots leading the variant to be described as Class B (“potentially less severe”, indicating that this variant may impact protein function (PMID:18425781)(PS3). REVEL Score = 0.952 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 180144, 2 star review status) with 5 submitters classifying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PS3, PP4_Moderate, PM3, PM2_Supporting, PP3 -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jul 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.92		Gain of disorder (P = 0.0121);Gain of disorder (P = 0.0121);
MVP		1.0
MPC		0.68
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.98

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: rs121907940; hg19: chr17-78081636;