17-80105860-G-T

Variant names:

• chr17-80105860-G-T
• rs530478036
• NM_000152.5:c.658G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PM2_Supporting BP4 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.658G>T variant is GAA is a missense variant that is predicted to result in the substitution of valine by leucine at amino acid 220 (p.Val220Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00075 (15/19928 alleles) in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS-7 cells, this variant results in normal GAA activity, and the protein is normally synthesized and/or processed (PMID 22644586) (BS3_Supporting). The computational predictor REVEL gives a score of 0.305 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). The variant has been reported in an individual with either suspected Pompe disease or a known carrier, but further details are not available (PMID 22644586). There is a ClinVar entry for this variant (Variation ID: 255365). While there is conflicting evidence, overall, the benign evidence, including functional studies (BS3_Supporting) and in silico data (BP4), outweighs the pathogenic evidence (PM2_Supporting). Therefore, the variant has been classified as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, BP4, BS3_Supporting (modified classification: likely benign, approved by ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 4, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814955/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:2
• Conservation: PhyloP100: -1.07
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.658G>T	p.Val220Leu	missense	Exon 3 of 20	NP_000143.2
	GAA	NM_001079803.3		c.658G>T	p.Val220Leu	missense	Exon 4 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.658G>T	p.Val220Leu	missense	Exon 3 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.658G>T	p.Val220Leu	missense	Exon 3 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.658G>T	p.Val220Leu	missense	Exon 4 of 21	ENSP00000374665.3
	GAA	ENST00000714054.1		c.-144G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	ENSP00000519344.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000817 AC: 20 AN: 244662 AF XY: 0.0000676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000762

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000461 AC: 67 AN: 1453252 Hom.: 0 Cov.: 56 AF XY: 0.0000526 AC XY: 38 AN XY: 722900

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5426

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1110622

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:3 Benign:1

Apr 04, 2023

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.658G>T variant is GAA is a missense variant that is predicted to result in the substitution of valine by leucine at amino acid 220 (p.Val220Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00075 (15/19928 alleles) in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS-7 cells, this variant results in normal GAA activity, and the protein is normally synthesized and/or processed (PMID 22644586) (BS3_Supporting). The computational predictor REVEL gives a score of 0.305 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). The variant has been reported in an individual with either suspected Pompe disease or a known carrier, but further details are not available (PMID 22644586). There is a ClinVar entry for this variant (Variation ID: 255365). While there is conflicting evidence, overall, the benign evidence, including functional studies (BS3_Supporting) and in silico data (BP4), outweighs the pathogenic evidence (PM2_Supporting). Therefore, the variant has been classified as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, BP4, BS3_Supporting (modified classification: likely benign, approved by ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 4, 2023).

Sep 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 220 of the GAA protein (p.Val220Leu). This variant is present in population databases (rs530478036, gnomAD 0.07%). This missense change has been observed in individual(s) with GAA-related disease (PMID: 22644586). ClinVar contains an entry for this variant (Variation ID: 255365). 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 not expected to disrupt GAA protein function. Experimental studies have shown that this missense change does not substantially affect GAA function (PMID: 22644586). 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.

Cardiovascular phenotype Uncertain:1

Feb 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V220L variant (also known as c.658G>T), located in coding exon 2 of the GAA gene, results from a G to T substitution at nucleotide position 658. The valine at codon 220 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in a cohort of known or suspected Pompe disease cases; however, studies suggested no significant functional impact (Kroos M et al. Hum Mutat, 2012 Aug;33:1161-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.022
DANN	Benign	0.71
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.27	N
PhyloP100		-1.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.99	N
REVEL	Uncertain	0.30
Sift	Benign	0.79	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.34		Loss of sheet (P = 0.1398)
MVP		0.33
MPC		0.11
ClinPred		0.0083	T
GERP RS		-10
Varity_R		0.15
gMVP		0.52
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs530478036; hg19: chr17-78079659;