rs368438393
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP3PP4PM3_StrongPS3PM5PM2
This summary comes from the ClinGen Evidence Repository: This variant, c.1933G>A (p.Asp645Asn), is a missense change which has been reported in least 11 individuals with deficient GAA activity meeting the ClinGen LSD VCEP's specifications for PP4 (PMIDs 9535769, 15145338, 16860134, 17723315, 23601496, 25139343, 26497565). Five of these individuals are homozygous for the variant have been reported to have infantile onset Pompe disease (PMIDs 16860134, 25139343, 26497565). This variant was also found in two patients who meet PP4 specifications, in compound heterozygosity, phase not confirmed, with a unique pathogenic variant in GAA, either c.2501_2502del or c.2242dup (PMIDs 9535769, 23601496). Based on data from homozygous and compound heterozygous patients, PM3_Strong is met. Additional compound heterozygous cases have been reported but the in trans data has been used in the assessment of the second variant and therefore is not included here in order to avoid circular logic (PMIDs 15145338, 17723315, 26497565). Other cases were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 18429042, 25455803, 27927596, 29122469, 30105547, 30155607). The highest population minor allele frequency in gnomAD is 0.00007 in the African population, meeting PM2. When expressed in GAA-deficient fibroblasts and COS cells, this variant results in virtually no GAA activity (PMIDs 9535769, 15145338), meeting PS3. The score for the in silico meta-predictor, REVEL, is 0.868 suggesting that the variant impacts the function of GAA, meeting PP3. Three other amino acid changes have been reported in patients with Pompe disease at the same amino acid position (c.1933G>C (p.Asp645His), c.1933G>T (p.Asp645Tyr), c.1935C>A (p.Asp645Glu). At least one of these variants, c.1935C>A (p.Asp645Glu), is pathogenic, meeting PM5. In summary, this variant meets the criteria to be specified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PM5, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273892/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
Publications
- glycogen storage disease IIInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
- glycogen storage disease due to acid maltase deficiency, infantile onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- glycogen storage disease due to acid maltase deficiency, late-onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000825 AC: 2AN: 242414 AF XY: 0.0000152 show subpopulations
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1458274Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 725104 show subpopulations
Age Distribution
GnomAD4 genome 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74352 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:11
Variant summary: GAA c.1933G>A (p.Asp645Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 86510 control chromosomes (ExAC). c.1933G>A has been reported in the literature in compound heterozygous or homozygous state in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Huie 1998, Prater 2012, McCready 2007). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Huie 1998, Prater 2012, McCready 2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 645 of the GAA protein (p.Asp645Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Pompe disease (PMID: 9535769, 15145338, 17723315, 18429042, 20830524, 23787031). ClinVar contains an entry for this variant (Variation ID: 188728). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 9535769, 15145338, 17723315, 20830524). For these reasons, this variant has been classified as Pathogenic. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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This variant, c.1933G>A (p.Asp645Asn), is a missense change which has been reported in least 11 individuals with deficient GAA activity meeting the ClinGen LSD VCEP's specifications for PP4 (PMIDs 9535769, 15145338, 16860134, 17723315, 23601496, 25139343, 26497565). Five of these individuals are homozygous for the variant have been reported to have infantile onset Pompe disease (PMIDs 16860134, 25139343, 26497565). This variant was also found in two patients who meet PP4 specifications, in compound heterozygosity, phase not confirmed, with a unique pathogenic variant in GAA, either c.2501_2502del or c.2242dup (PMIDs 9535769, 23601496). Based on data from homozygous and compound heterozygous patients, PM3_Strong is met. Additional compound heterozygous cases have been reported but the in trans data has been used in the assessment of the second variant and therefore is not included here in order to avoid circular logic (PMIDs 15145338, 17723315, 26497565). Other cases were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 18429042, 25455803, 27927596, 29122469, 30105547, 30155607). The highest population minor allele frequency in gnomAD is 0.00007 in the African population, meeting PM2. When expressed in GAA-deficient fibroblasts and COS cells, this variant results in virtually no GAA activity (PMIDs 9535769, 15145338), meeting PS3. The score for the in silico meta-predictor, REVEL, is 0.868 suggesting that the variant impacts the function of GAA, meeting PP3. Three other amino acid changes have been reported in patients with Pompe disease at the same amino acid position (c.1933G>C (p.Asp645His), c.1933G>T (p.Asp645Tyr), c.1935C>A (p.Asp645Glu). At least one of these variants, c.1935C>A (p.Asp645Glu), is pathogenic, meeting PM5. In summary, this variant meets the criteria to be specified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PM5, PP4. -
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The GAA c.1933G>A (p.Asp645Asn) variant has been reported in six studies and is found in a total of seven patients with infantile-onset Pompe disease (also known as glycogen storage disease, type II). The p.Asp645Asn variant was present in five patients in a compound heterozygous state and two patients in a homozygous state (Huie et al. 1998; Kroos et al. 2004; McCready et al. 2007; Pittis et al. 2008; Del Rizzo et al. 2010; Tan et al. 2015). In addition, two unaffected parents carried the variant in a heterozygous state (Kroos et al. 2004; Tan et al. 2015). Control data are unavailable for the p.Asp645Asn variant, which is reported at a frequency of 0.00023 in the African population of the Exome Sequencing Project, but this is based on one allele in a region of low sequence coverage. In vitro expression of the p.Asp645Asn variant in both SV40 immortalized fibroblasts (TR4912) and COS cells yielded low enzyme activity (Huie et al. 1998; Kroos et al. 2004). Based on the collective evidence, the p.Asp645Asn variant is classified as pathogenic for glycogen storage disease, type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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A homozygous missense variant in exon 14 of the GAA gene that results in the amino acid substitution of Asparagine for Aspartate at codon 645 was detected. The observed variant c.1933G>A (p.Asp645Asn) has not been reported in the 1000 genomes and has a MAF of 0.0008% in the gnomAD databases. The in-silico prediction of the variant are damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
The p.Asp645Asn variant in GAA has been reported in at least 29 individuals with Glycogen Storage Disease II (PMID: 9535769, 10338092, 15145338, 16860134, 18429042, 17723315, 20830524, 26497565, 23601496, 25139343, 30155607, 19862843, 27927596, 25455803, 30105547, 29122469). This variant has been identified in 0.007% (1/15154) of African chromosomes and 0.001% (1/109242) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The presence of this variant in homozygotes and in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp645Asn variant is pathogenic (PMID: 20830524, 17723315, 16860134, 15145338, 26497565, 25139343, 9535769, 23601496). This variant has also been reported likely pathogenic by Counsyl and pathogenic by GeneDx, Illumina, Invitae, and Integrated Genetics in ClinVar (Variation ID: 188728). In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Asp645Asn variant may impact protein function based on GAA activity assays and a Western Blot (PMID: 15145338, 9535769). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals with Glycogen Storage Disease II and homozygous or heterozygous for this variant based on very low GAA activity, consistent with disease (PMID: 20830524, 17723315, 16860134, 15145338, 26497565, 25139343, 9535769, 23601496). Three additional variants at the the same position (p.Asp645Glu, p.Asp645Tyr, and p.Asp645His) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 4029, 189013, 556386). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with reported pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II, in vitro functional studies, and multiple missense variants associated with disease at the same position. ACMG/AMP Criteria applied: PM3_Strong, PM5_Strong, PS3, PM2, PP3, PP4 (Richards 2015). -
not provided Pathogenic:2
The D645N pathogenic variant in the GAA gene has been previously reported, in both the compound heterozygous and homozygous state, in patients with infantile GSDII (Huie et al., 1998; Del Rizzo et al., 2010). Functional studies demonstrate D645N results in significantly reduced GAA enzyme activity compared to wild type controls (Huie et al., 1998). The D645N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and different missense variants at the same position (D645H/Y/E) have been previously reported in association with GSDII (Lin et al., 1995; Gort et al., 2007; Hermans et al., 1993). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at