rs192679574

chr17-80118646-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000152.5(GAA):c.2647-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,611,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.5028
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: -1.69

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80118646-G-A is Pathogenic according to our data. Variant chr17-80118646-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551106.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2647-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2647-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249470 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134914

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459478 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 726068

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74412

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 12, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.2647-7G>A variant in GAA has been reported in at least 9 Italian individuals with glycogen storage disease, segregated with disease in 9 affected relatives from 1 family (PMID: 24107549), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.003% (4/128816) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs192679574). 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 (Variation: 551106) as Likely Pathogenic by Counsyl. In vitro functional studies provide some evidence that the c.2647-7G>A variant may slightly impact protein function by showing presence of alternatively spliced transcripts that result in NMD (PMID: 24107549). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. The nucleotide at position 2647-7 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. Additional computational tools do suggest an impact to splicing resulting in a cryptic acceptor splice site that causes a frameshift. However, this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in muscle being <10% of wild type, consistent with disease (PMID: 24107549). Additionally, the presence of this variant in combination with a reported pathogenic variant p.Arg40Ter (VariationID: 426593; PMID: 24107549) in seven siblings with glycogen storage disease slightly increases the likelihood that the c.2647-7G>A 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: PM3_supporting, PM2, PP4, PP3, PS3_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change falls in intron 18 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. This variant is present in population databases (rs192679574, gnomAD 0.003%). This variant has been observed in individual(s) with late-onset glycogen storage disease (PMID: 24107549). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551106). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2022	Variant summary: GAA c.2647-7G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3 prime acceptor site. One predict the variant weakens a canonical 3 prime acceptor site. Four predict the variant creates a cryptic 3 prime acceptor site. Sampaolo_ 2013 have demostrated this variant leads to a reduction in wild type mRNA levels consistent with the abolishment of the canonical 3' acceptor site. The variant allele was found at a frequency of 1.6e-05 in 249470 control chromosomes (gnomAD). c.2647-7G>A has been reported in the literature in multiple compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and variant segregated with the disease (Sampaolo_GAA_OJRD_2013). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 13, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2021	This sequence change is a substitution in intron 18, c.2647-7G>A. This sequence change has been described in the gnomAD database with a low frequency of 0.003% in the south Asian and non-Finnish European subpopulations (rs192679574). This sequence change has been previously described in a family with late-onset Pompe disease and segregates with the disease phenotype (PMID: 24107549). Functional studies show c.2647-7G>A causes a splicing defect (PMID: 24107549). Based on these evidence, the c.2647-7G>A variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	16
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs192679574; hg19: chr17-78092445;