rs766074609
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePM3_StrongPP3PM2_SupportingPS3_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1064T>C variant in GAA is a missense variant predicted to cause substitution of leucine to proline at amino acid 355 (p.Leu355Pro). This variant has been reported in over 20 individuals with Pompe disease including at least 9 individuals with documented laboratory values showing GAA deficiency (PP4_Moderate) (PMIDs 14972326, 17213836, 17723315, 17213836, 23632174, 24016645, 30595407)(PP4_Moderate). The variant is homozygous in multiple patients (PMIDs 14972326, 16917947, 17213836, 17573812, 17723315, 18429042, 22658377, 23787031, 24016645, 30023291, 33325062). Three individuals are compound heterozygous for the variant and another variant that has been assessed as pathogenic by the ClinGen LSD VCEP; c.-32-13T>G in two patients (PMIDs 17643989, 21803581), and confirmed in trans with c.670C>T (p.Arg224Trp) in another patient (PMID 23632174; (PM3_Strong). p.Leu355Pro has also been reported in individuals with Pompe disease who are compound heterozygous for c.2041-2A>C (PMID 33325062), c.2303C>G (p.Pro768Arg) (PMID 17027861), c.1210G>A (p.Asp404Asn) (PMID 22658377, 23787031), c.1120T>C (p.Cys374Arg) (PMID 14695532), c.1927G>A (p.Gly643Arg) (PMID 18429042), c.1106T >C (p.Leu369Pro) (PMID 23430493), and c.380G>T (p.Cys127Phe) (PMID 24016645). The in trans data from these patients will be used in the assessment of the other variant and was not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34580) in the Latino population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in absent GAA activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 284093, 2 star review status) with four submitters each classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815136/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250882Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135824
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461082Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4AN XY: 726856
GnomAD4 genome
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:9
The p.Leu355Pro variant in GAA has been reported in 23 individuals (including 4 Italian, 4 Portuguese, 2 Israeli, 2 Columbian, 1 German, 1 Turkish, and 1 Syrian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 16917947, 14972326, 18429042, 17643989, 14695532, 17723315, 23632174, 23430493, 23787031, 24016645, 30023291, 17213836, 17573812, 30595407), and has also been reported pathogenic by Counsyl and EGL in ClinVar (Variation ID: 284093). This variant has been identified in 0.003% (1/34580) of Latino chromosomes and 0.001% (1/113290) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766074609). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Leu355Pro variant may impact GAA processing and activity (PMID: 14695532, 14972326). 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 Leucine (Leu) at position 355 is not conserved in one mammal species and more evolutionary distant species, slightly raising the possibility that a change at this position may be tolerated. The presence of this variant in the homozygous state and in combination with pathogenic and likely variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Leu355Pro variant is pathogenic (PMID: 23430493, 24016645, 23632174, 17723315, 14972326). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 23430493, 24016645, 23632174, 17723315, 14972326). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant and multiple occurrences with pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP3, PP4 (Richards 2015). -
The NM_000152.5:c.1064T>C variant in GAA is a missense variant predicted to cause substitution of leucine to proline at amino acid 355 (p.Leu355Pro). This variant has been reported in over 20 individuals with Pompe disease including at least 9 individuals with documented laboratory values showing GAA deficiency (PP4_Moderate) (PMIDs 14972326, 17213836, 17723315, 17213836, 23632174, 24016645, 30595407)(PP4_Moderate). The variant is homozygous in multiple patients (PMIDs 14972326, 16917947, 17213836, 17573812, 17723315, 18429042, 22658377, 23787031, 24016645, 30023291, 33325062). Three individuals are compound heterozygous for the variant and another variant that has been assessed as pathogenic by the ClinGen LSD VCEP; c.-32-13T>G in two patients (PMIDs 17643989, 21803581), and confirmed in trans with c.670C>T (p.Arg224Trp) in another patient (PMID 23632174; (PM3_Strong). p.Leu355Pro has also been reported in individuals with Pompe disease who are compound heterozygous for c.2041-2A>C (PMID 33325062), c.2303C>G (p.Pro768Arg) (PMID 17027861), c.1210G>A (p.Asp404Asn) (PMID 22658377, 23787031), c.1120T>C (p.Cys374Arg) (PMID 14695532), c.1927G>A (p.Gly643Arg) (PMID 18429042), c.1106T >C (p.Leu369Pro) (PMID 23430493), and c.380G>T (p.Cys127Phe) (PMID 24016645). The in trans data from these patients will be used in the assessment of the other variant and was not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34580) in the Latino population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in absent GAA activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 284093, 2 star review status) with four submitters each classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved August 17, 2021) -
The c.1064T>C;p.(Leu355Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 284093; PMID: 14695532; 14972326; 24016645; 23787031; 23632174; 23430493) -.PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 14972326) - PS3_supporting. The variant is present at low allele frequencies population databases (rs766074609– gnomAD 0.00007972%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu355Pro) was detected in trans with a pathogenic variant (PMID: 14695532; 14972326; 24016645; 23787031; 23632174; 23430493) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Variant summary: GAA c.1064T>C (p.Leu355Pro) results in a non-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 8e-06 in 250882 control chromosomes (gnomAD). c.1064T>C has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Pittis_2008, Nino_2012). One of these publications also reported experimental evidence evaluating an impact on protein function, and found the complete absence of enzyme activity and lack protein product in transiently transfected COS cells (Hermans_2004). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters, including one expert panel (ClinGen), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 355 of the GAA protein (p.Leu355Pro). This variant is present in population databases (rs766074609, gnomAD 0.003%). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 14972326, 18429042, 23430493, 23632174). 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: 284093). 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: 14695532, 14972326). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:3
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Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 14695532, 14972326); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24016645, 14972326, 34530085, 23632174, 29422078, 18429042, 17643989, 30314719, 31589614, 14695532, 23430493, 23787031, 38958145, 39020349) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at