rs1555601773

Positions:

• chr17-80113309-CA-GG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2132_2133delinsGG variant in GAA is a multinucleotide variant predicted to cause substitution of threonine by arginine at amino acid 711 (p.Thr711Arg). The same amino acid change, resulting from one of the two nucleotide changes observed in this multinucleotide variant, c.2132C>G, has been reported in a patient with Pompe disease (PMID:20080426, 31342611). However, this other variant has conflicting evidence for pathogenicity based on guidelines by the ClinGen LSD VCEP (PMID:18425781). The minor allele frequency of the c.2132C>G variant in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population, but was only seen in phase with c.2133A>G in 23 of the 24 heterozygotes reported in gnomAD v2.1.1. Therefore, the highest possible population minor allele frequency in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population (none of the population data codes are met). The computational predictors PROVEAN, Mutation Taster, and MutPredIndel suggest that this variant has a deleterious effect on the GAA gene, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 456391, 1 star review status) with 2 submitters, 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658658713/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 4.87

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 1 ACMG points.

• PP3: 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.2132_2133delinsGG	p.Thr711Arg	missense_variant	15/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2132_2133delinsGG	p.Thr711Arg	missense_variant	15/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 19, 2022	The NM_000152.5:c.2132_2133delinsGG variant in GAA is a multinucleotide variant predicted to cause substitution of threonine by arginine at amino acid 711 (p.Thr711Arg). The same amino acid change, resulting from one of the two nucleotide changes observed in this multinucleotide variant, c.2132C>G, has been reported in a patient with Pompe disease (PMID: 20080426, 31342611). However, this other variant has conflicting evidence for pathogenicity based on guidelines by the ClinGen LSD VCEP (PMID: 18425781). The minor allele frequency of the c.2132C>G variant in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population, but was only seen in phase with c.2133A>G in 23 of the 24 heterozygotes reported in gnomAD v2.1.1. Therefore, the highest possible population minor allele frequency in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population (none of the population data codes are met). The computational predictors PROVEAN, Mutation Taster, and MutPredIndel suggest that this variant has a deleterious effect on the GAA gene, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 456391, 1 star review status) with 2 submitters, 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 711 of the GAA protein (p.Thr711Arg). This variant is present in population databases (no rsID available, gnomAD 0.009%). A different variant (c.2132C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 18211760, 23884227, 28394184). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 456391). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555601773; hg19: chr17-78087108;