rs1555600235
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM4_SupportingPP5_Strong
The NM_000152.5(GAA):c.1320_1322del(p.Met440del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 33)
Consequence
GAA
NM_000152.5 inframe_deletion
NM_000152.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.49
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000152.5
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000152.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 17-80108816-CATG-C is Pathogenic according to our data. Variant chr17-80108816-CATG-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 526518.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr17-80108816-CATG-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1320_1322del | p.Met440del | inframe_deletion | 8/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1320_1322del | p.Met440del | inframe_deletion | 8/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:1Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Nov 03, 2022 | The NM_000152.5:c.1317delGAT or c.1320_1322delGAT variant is predicted to cause a change in the length of protein due to inframe deletion of one amino acid, Met440 in a non repeat region (PM4_Supporting). This variant is documented in NBS-Pompe program from Japan (PMID: 31076647). One LOPD patient from China was reported to be compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.2238G>C (p.Trp746Cys)(PM3_supporting). This patient had documented deficiency of GAA activity (PMID: 35071497) (PP4_moderate). The variant is absent in gnomAD v2.1.1 (PM2_supporting). The results of in silico predictors were conflicting. To our knowledge, no functional studies have been performed on this variant. There is a ClinVar entry for this variant (Variant ID: 526518). Due to insufficient evidence this variant is classified as of uncertain significance for Pompe disease based on ACMG/AMP criteria applied, as specified by LSD VCEP (specification version 2.0). Criteria applied: criteria: PM2_supporting; PM3_supporting, PM4_Supporting, PP4_moderate. (Classification approved by the ClinGen LSD VCEP on Nov 3, 2022). - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 01, 2019 | 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. This variant has been observed in individual(s) with Pompe disease (PMID: 25526786, 28394184, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1315_1317delATG in the literature. ClinVar contains an entry for this variant (Variation ID: 526518). This variant is not present in population databases (ExAC no frequency). This variant, c.1320_1322del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Met440del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at