rs765362308

chr17-80112056-C-Gchr17-80112056-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.1710C>G(p.Asn570Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,996 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N570S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.49

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 1 benign, 11 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 chr17-80112055-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2793202.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-80112056-C-G is Pathogenic according to our data. Variant chr17-80112056-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555153.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80112056-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1710C>G	p.Asn570Lys	missense_variant	12/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1710C>G	p.Asn570Lys	missense_variant	12/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2021	Variant summary: GAA c.1710C>G (p.Asn570Lys) 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 was absent in 251344 control chromosomes (gnomAD). c.1710C>G has been reported in combination with another GAA variant in the literature in individuals affected with infantile-onset Pompe disease or late-onset Pompe disease (Banugaria_2011, Kishnani_2019, Vanherpe_2020, De Groot_2021). These data indicate that the variant is likely to be associated with disease. At least one functional paper reports experimental evidence evaluating an impact on protein function and this variant results in reducing alpha-glucosidase activity in transfected cells compared to WT activity. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 570 of the GAA protein (p.Asn570Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22658377, 29122469, 31086307). ClinVar contains an entry for this variant (Variation ID: 555153). 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: 22644586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asn570Lys variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29122469, 22658377, 18425781, 22538254) and has been identified in 0.011% (1/8702) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765362308). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as a VUS by Counsyl (VariationID: 555153). In vitro functional studies using COS-7 cells transfected with the variant provide some evidence that the p.Asn570Lys variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 17151339). Computational prediction tools do not provide strong support for or against an impact to the protein, but the Asn at position 570 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, the presence of this variant in combination with reported pathogenic variant p.Arg584Ter (VariationID: 4034, PMID: 29122469, 22658377, 22538254) and in an individual with glycogen storage disease II increases the likelihood that the p.Asn570Lys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM3_Supporting PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2022	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 02, 2021	The NM_000152.5:c.1710C>G (p.Asn570Lys) variant in GAA has a minor allele frequency in gnomAD of 0.0001149 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.9% GAA activity in cells and 0.5% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence is inconclusive, REVEL score = 0.662 which is lower than the LSD VCEP threshold for PP3 (>0.7) and is higher than the LSD VCEP threshold for BP4 (<0.5), and therefore does not meet either criterion. This variant was found in compound heterozygosity (phase unknown) with a pathogenic variant in GAA, c.2560C>T (p.Arg854Ter) in at least one patient with Pompe disease (PMID: 22538254, 22658377, 29122469, 31193175) and another patient with the pathogenic variant c.-32-13T>G and a rare synonymous variant c.1923G>A (p.Leu641=)(PMID: 32248831) (PM3_Supporting). At least two individuals has been reported with this variant and GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay/ were reported to be on enzyme replacement therapy for Pompe disease (PMID: 17151339, 22538254, 29122469, 32248831)( PP4_Moderate). There is a ClinVar entry for this variant (Variation ID: 555153; 2 star review status) with 2 submitters classifying the variant as a VUS and 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PS3_Moderate, PM3_Supporting, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.95	P;P
Vest4		0.87
MutPred		0.89		Gain of ubiquitination at N570 (P = 0.0351);Gain of ubiquitination at N570 (P = 0.0351);
MVP		0.97
MPC		0.54
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.94
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs765362308; hg19: chr17-78085855;