17-80108610-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM3PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1194+3G>C variant in GAA is located in the donor splice site consensus region of intron 7. The variant has been identified in four individuals, three with documented laboratory values showing GAA activity in the affected range in dried blood spots (Clinical Diagnostic Laboratories, PMID:33073003). One of these individuals is reported to be symptomatic, with GAA activity in the affected range in dried blood spots, and absence of known pseudodeficiency variants (PP4_Moderate); this individual is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP - c.1210G>A (p.Asp404Asn), ClinVar Variation ID: 657348, SCV002817441.1, confirmed in trans (Clinical Laboratory) (PM3). The other individuals were identified on newborn screen will not be included because it is unknown if they are clinically symptomatic or if the enzyme deficiency could be the result of pseudodeficiency. These individuals are compound heterozygous for the variant and either c.1781G>A (p.Arg594His) (in trans based on testing of one parent), ClinVar Variation ID: 972747; SCV002817431.1; c.1841C>A (p.Thr614Lys), ClinVar Variation ID: 167113, SCV001371751.1, phase unknown (Clinical Laboratory); or c.1827del (ClinVar Variation ID: 188936, SCV001371738.1) (Clinical Laboratory). The highest population minor allele frequency in gnomAD v2.1.1. is 0.0003149 (40/127034 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor SpliceAI gives a score of 0.17 for loss of the intron 7 donor splice site, and a score of 0.31 for loss of the intron 6 acceptor splice site suggesting possible effect on splicing but not meeting the current SpliceAI threshold (>0.5) of the ClinGen Lysosomal Diseases VCEP (PP3 not met). There is a ClinVar entry for this variant (Variation ID: 198393). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA247031/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 splice_donor_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1194+3G>C | splice_donor_region_variant, intron_variant | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1194+3G>C | splice_donor_region_variant, intron_variant | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000169 AC: 42AN: 247840Hom.: 0 AF XY: 0.000171 AC XY: 23AN XY: 134808
GnomAD4 exome AF: 0.000264 AC: 385AN: 1460446Hom.: 0 Cov.: 39 AF XY: 0.000241 AC XY: 175AN XY: 726550
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74358
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:3Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 17, 2023 | The GAA c.1194+3G>C variant (rs368539333) is reported in the literature in compound heterozygous individuals with reduced GAA activity identified by newborn screening (Burton 2020, Ficicioglu 2020). This variant is reported in ClinVar (Variation ID: 198393) and is found in the general population with an overall allele frequency of 0.0158% (44/279,222 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. The c.1194+3G>C variant is classified as likely pathogenic by the ClinGen lysosomal diseases variant curation expert panel, however, internal data was cited and could not be independently verified. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to lysosomal diseases VCEP: https://clinicalgenome.org/affiliation/50009 Burton BK et al. Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants. Int J Neonatal Screen. 2020 Jan 21;6(1):4. PMID: 33073003. Ficicioglu C et al. Newborn Screening for Pompe Disease: Pennsylvania Experience. Int J Neonatal Screen. 2020 Nov 13;6(4):89. PMID: 33202836. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change falls in intron 7 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs368539333, gnomAD 0.03%). This variant has been observed in individual(s) with biochemical features of Pompe disease (PMID: 33073003, 33202836; Invitae; External communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198393). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | May 21, 2024 | The NM_000152.5:c.1194+3G>C variant in GAA is located in the donor splice site consensus region of intron 7. The variant has been identified in four individuals, three with documented laboratory values showing GAA activity in the affected range in dried blood spots (Clinical Diagnostic Laboratories, PMID: 33073003). One of these individuals is reported to be symptomatic, with GAA activity in the affected range in dried blood spots, and absence of known pseudodeficiency variants (PP4_Moderate); this individual is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP - c.1210G>A (p.Asp404Asn), ClinVar Variation ID: 657348, SCV002817441.1, confirmed in trans (Clinical Laboratory) (PM3). The other individuals were identified on newborn screen will not be included because it is unknown if they are clinically symptomatic or if the enzyme deficiency could be the result of pseudodeficiency. These individuals are compound heterozygous for the variant and either c.1781G>A (p.Arg594His) (in trans based on testing of one parent), ClinVar Variation ID: 972747; SCV002817431.1; c.1841C>A (p.Thr614Lys), ClinVar Variation ID: 167113, SCV001371751.1, phase unknown (Clinical Laboratory); or c.1827del (ClinVar Variation ID: 188936, SCV001371738.1) (Clinical Laboratory). The highest population minor allele frequency in gnomAD v2.1.1. is 0.0003149 (40/127034 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor SpliceAI gives a score of 0.17 for loss of the intron 7 donor splice site, and a score of 0.31 for loss of the intron 6 acceptor splice site suggesting possible effect on splicing but not meeting the current SpliceAI threshold (>0.5) of the ClinGen Lysosomal Diseases VCEP (PP3 not met). There is a ClinVar entry for this variant (Variation ID: 198393). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) - |
not provided Pathogenic:1Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2023 | Identified with a second variant in GAA in individuals with slightly reduced GAA activity identified on newborn screening for GSDII; these individuals were not clinically symptomatic at the time of report (Ficicioglu C et al., 2020; Burton BK et al., 2020); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 33073003, 33202836) - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 22, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 19, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | GAA: BP4 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2023 | Variant summary: GAA c.1194+3G>C alters a 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: One predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. Three predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00017 in 247840 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00017 vs 0.0042), allowing no conclusion about variant significance. c.1194+3G>C has been reported in the literature during newborn screening in patients with low GAA activity and second pathogenic variants (Burton_2019, Ficicioglu_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have classified the variant: six submitters have classified the variant as VUS while an expert panel has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at