17-80104910-T-C

Position:

• chr17-80104910-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145781/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.72 (39941 hom., cov: 34)
  • Exomes 𝑓: 0.74 (404400 hom.)
• Consequence: GAA ENST00000302262.8 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:19
• Conservation: PhyloP100: 2.04

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 Benign. Variant got -8 ACMG points.

• BA1: 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.324T>C	p.Cys108=	synonymous_variant	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.324T>C	p.Cys108=	synonymous_variant	2/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109760 AN: 152070 Hom.: 39921 Cov.: 34

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.708

GnomAD3 exomes AF: 0.723 AC: 178297 AN: 246688 Hom.: 65703 AF XY: 0.738 AC XY: 98988 AN XY: 134130

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.628

Gnomad SAS exome AF: 0.818

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.756

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.743 AC: 1084167 AN: 1459628 Hom.: 404400 Cov.: 80 AF XY: 0.746 AC XY: 541839 AN XY: 726082

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.526

Gnomad4 ASJ exome AF: 0.802

Gnomad4 EAS exome AF: 0.683

Gnomad4 SAS exome AF: 0.813

Gnomad4 FIN exome AF: 0.799

Gnomad4 NFE exome AF: 0.745

Gnomad4 OTH exome AF: 0.749

GnomAD4 genome AF: 0.722 AC: 109824 AN: 152188 Hom.: 39941 Cov.: 34 AF XY: 0.721 AC XY: 53629 AN XY: 74414

Gnomad4 AFR AF: 0.696

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.788

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.814

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.751

Gnomad4 OTH AF: 0.708

Alfa AF: 0.742 Hom.: 51093

Bravo AF: 0.704

Asia WGS AF: 0.732 AC: 2546 AN: 3478

EpiCase AF: 0.753

EpiControl AF: 0.756

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:19

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Benign:7

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 21, 2020	The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2017	p.Cys108Cys in exon 3 of GAA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 82% (13463/16390) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1800300). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Uncertain:1 Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 82.142% in ExAC) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2017	Variant summary: The GAA c.324T>C (p.Cys108Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 86202/117014 control chromosomes (32095 homozygotes) at a frequency of 0.7366811, indicating the C allele is the major allele. This frequency is approximately 175 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant has been classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.0
DANN	Benign	0.60

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: rs1800300; hg19: chr17-78078709; COSMIC: COSV56406822; COSMIC: COSV56406822;