rs374143224

chr17-80112966-G-A

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.1979G>A(p.Arg660His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,609,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging 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. R660C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 9.86

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr17-80112965-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 558604.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 17-80112966-G-A is Pathogenic according to our data. Variant chr17-80112966-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189172.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80112966-G-A is described in Lovd as [Pathogenic]. Variant chr17-80112966-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-80112966-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1979G>A	p.Arg660His	missense_variant	14/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1979G>A	p.Arg660His	missense_variant	14/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000250 AC: 6 AN: 240400 Hom.: 0 AF XY: 0.0000229 AC XY: 3 AN XY: 130940

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.0000887

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1457548 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 724832

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000677

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: 0.0000234

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000972 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 04, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 01, 2022	The NM_000152.5: c.1979G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 660 (p.Arg660His). More than nine individuals with features consistent with Pompe disease have been reported with this variant. Of these patients 3 probands (and two siblings) have documented laboratory values indicating GAA deficiency in the affected range in dried blood spot, or muscle, or <1% activity in cultured skin fibroblasts (PMID: 21484825, 25037089, 27649523), and three probands are reported to have low GAA activity and to be on enzyme replacement therapy (PP4_Moderate). Six patients are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP. For two patients, the second variant was confirmed in trans by parental testing - c.525delT (PMID: 30559630, possibly same case in PMID: 30214072), and c.670C>T (p.Arg224Trp) (PMID: 14643388) – and in four patients the phase of the second variant is unconfirmed - c.655G>A (p.Gly219Arg) (PMID: 29122469), c.1082C>T (p.Pro361Leu) (PMID: 21484825), c.1998C>T (p.Arg600Cys) (PMID: 14643388), and c.2560C>T (p.Arg854Ter) (PMID: 30214072). Two homozygous siblings have also been reported (PMID: 27649523) (PM3_Very Strong). Two probands have been reported who are compound heterozygous for the variant and either c.-32-17_-32-10del8ins30 (PMID: 25037089; two affected siblings), or c.1114C>T (p.His372Tyr) (PMID: 30214072). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (6/23566) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In two independent studies, in which the variant was expressed in COS cells, the GAA activity was <2% wild type, indicating that the variant has a damaging effect on GAA function (PS3_Supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant, c.1978C>T (p.Arg660Cys), has been reported at this position. p.Arg660His will be used to support the classification of p.Arg660Cys and thus PM5 is not applied here, in order to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 189172; 2 star review status) with nine submitters classifying the variant as pathogenic, and three as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Approved by LSD VCEP on Feb 15, 2022). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2018	Variant summary: GAA c.1979G>A (p.Arg660His) 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 0.00013 in 31000 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.1979G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Pipo_2003, Bernstein_2010, Bali_2011). These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on enzyme activity (Pipo_2003, Bali_2011). The most pronounced variant effect results in <10% of normal activity. Three 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 660 of the GAA protein (p.Arg660His). 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 hypertrophic cardiomyopathy (HCM) and/or Pompe disease (PMID: 14643388, 20472203, 20638881, 21484825, 22521436, 22555271, 27649523). 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: 189172). 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: 14643388). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 15, 2021	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	Observed in multiple individuals with glycogen storage disease type II, who harbored a second GAA variant, in the published literature (Pipo et al., 2003; Bernstein et al., 2010, Burrow et al., 2010, Palermo et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as the variant impacts the function of the protein (Pipo et al., 2003); This variant is associated with the following publications: (PMID: 31086307, 31127727, 30559630, 33073007, 29122469, 14643388, 22555271, 22658377, 19862843, 22521436, 27649523, 21484825, 26402642, 30281819, 20472203, 20638881) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -

GAA-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The GAA c.1979G>A variant is predicted to result in the amino acid substitution p.Arg660His. This variant was reported in the homozygous and compound heterozygous states in multiple patients with Pompe disease (Nazari et al. 2017. PubMed ID: 27649523, Pipo et al. 2003. PubMed ID: 14643388, Kindel et al. 2012. PubMed ID: 22555271). In at least two patients carrying this variant, biochemical testing indicated GAA deficiency (Nazari et al. 2017. PubMed ID: 27649523). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. This variant was classified as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel and most laboratories in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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: rs374143224; hg19: chr17-78086765;