17-80108603-C-T

Position:

• chr17-80108603-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_Supporting PS3_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1190C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 397 (p.Pro397Leu). One patient with a diagnosis of Pompe disease has been reported with this variant, but GAA activity and clinical details were not available (PMID:30155607). This patient is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1781G>A (p.Arg594His) (PMID:30155607). The variant was also found in heterozygosity in individuals identified by newborn screening who also carried pseudodeficiency variants (PMID:31076647, 34922579). Although this variant has been reported multiple times, there is currently insufficient evidence to apply either PM3 or PP4. The highest population minor allele frequency in gnomAD v4 is 0.00002 (22/1111896 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.918 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: 456370). In summary, this variant currently meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on criteria specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PS3_Moderate, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815197/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:3
• Conservation: PhyloP100: 7.29

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 Uncertain_significance. Variant got 4 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.
• 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	c.1190C>T	p.Pro397Leu	missense_variant	7/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1190C>T	p.Pro397Leu	missense_variant	7/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 248010 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134890

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460482 Hom.: 0 Cov.: 38 AF XY: 0.0000193 AC XY: 14 AN XY: 726580

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: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000615 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 10, 2021	NM_000152.3(GAA):c.1190C>T(P397L) is a missense variant classified as a variant of uncertain significance in the context of Pompe disease. P397L has been observed in cases with relevant disease (PMID: 30155607, 31076647). Functional assessments of this variant are available in the literature (PMID: 22644586). P397L has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000152.3(GAA):c.1190C>T(P397L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 21, 2023	The NM_000152.5:c.1190C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 397 (p.Pro397Leu). One patient with a diagnosis of Pompe disease has been reported with this variant, but GAA activity and clinical details were not available (PMID: 30155607). This patient is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1781G>A (p.Arg594His) (PMID: 30155607). The variant was also found in heterozygosity in individuals identified by newborn screening who also carried pseudodeficiency variants (PMID: 31076647, 34922579). Although this variant has been reported multiple times, there is currently insufficient evidence to apply either PM3 or PP4. The highest population minor allele frequency in gnomAD v4 is 0.00002 (22/1111896 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.918 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: 456370). In summary, this variant currently meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on criteria specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PS3_Moderate, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023) -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Pro397Leu variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II in the literature but has been reported as a VUS by Invitae in ClinVar (Variation ID: 456370). This variant has been identified in 0.005% (6/111710) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776008078). 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 provide some evidence that the p.Pro397Leu variant may eliminate proteolytically activated protein from cells and impact GAA activity (PMID: 22644586). 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. 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 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2022	Variant summary: GAA c.1190C>T (p.Pro397Leu) 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 2.4e-05 in 248010 control chromosomes (gnomAD). c.1190C>T has been reported in the literature in at least two individuals with features of Glycogen Storage Disease, Type 2 (Pompe Disease): one compound heterozygous individual with a clinical diagnosis and one individual with reduced enzyme activity who harbored a complex pseudodeficiency allele (e.g. Semplicini_2018, Momosaki_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kroos_2012). The variant was associated with a normal amount of the precursor form of the protein in cell homogenates, but levels of the intermediate and mature forms of the protein were undetectable and the variant resulted in little to no enzymatic activity compared to the WT protein in vitro. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 397 of the GAA protein (p.Pro397Leu). This variant is present in population databases (rs776008078, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of GAA-related conditions (PMID: 30155607, 31076647). ClinVar contains an entry for this variant (Variation ID: 456370). 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: 22644586). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 27, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.5	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.85		Loss of methylation at R393 (P = 0.0868);Loss of methylation at R393 (P = 0.0868);
MVP		1.0
MPC		0.55
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs776008078; hg19: chr17-78082402; COSMIC: COSV56412328; COSMIC: COSV56412328;