ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1802C>T (p.Ser601Leu)

gnomAD frequency: 0.00001  dbSNP: rs374470794
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001242470 SCV002032130 pathogenic Glycogen storage disease, type II 2021-09-07 reviewed by expert panel curation The NM_000152.5:c. c.1802C>T variant in GAA is a missense variant predicted to cause substitution of serine by leucine at amino acid 601 (p.Ser601Leu). At least eight patients with this variant have been reported to have Pompe disease including three with clinical features consistent with infantile onset Pompe disease and on enzyme replacement therapy (PMID 22538254, 30023291), and one with GAA deficiency reported in the affected range in lymphocytes (PMID 22676651), as well as four patients reported to be diagnosed with the condition (PMID 28394184) (PP4_Moderate). Of note, in one patient, with features of infantile onset Pompe disease and on ERT, the variant was reported to be in cis with pseudodeficiency variants c.1726G>A and c.2065G>A (PMID 22538254). Of these patients, four were compound heterozygous for the variant and a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PMID 22676651, 28394184, 30023291) One patient was homozygous for the variant (PMID 30023291) (PM3_Strong). In addition, three patients were compound heterozygous for the variant and a missense variant (PMID 22538254, 28394184). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD is 0.00064 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0.5% wild type GAA activity in cells and medium, and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe"). This indicates that the variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1802C>G (p.Ser601Trp), in the same codon has been reported in patients with Pompe disease (PMID 17056254, 29422078). However, the data for p.Ser601Leu will be used in the assessment of p.Ser601Trp and therefore PM5 is not met here in order to avoid circular logic (PM5 not met). The is a ClinVar entry for this variant (Variation ID: 194154). In summary, this variant meets the criteria to be classified at pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specification version 2.0): PM3_Strong; PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3. (Classification approved on August 17, 2021)
Eurofins Ntd Llc (ga) RCV000174449 SCV000225755 pathogenic not provided 2014-11-19 criteria provided, single submitter clinical testing
Invitae RCV001242470 SCV001415562 pathogenic Glycogen storage disease, type II 2023-10-14 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 601 of the GAA protein (p.Ser601Leu). This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individuals with Pompe disease (PMID: 22252923, 28394184). ClinVar contains an entry for this variant (Variation ID: 194154). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001242470 SCV001422902 likely pathogenic Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter curation The p.Ser601Leu variant in GAA has been reported in 2 Saudi Arabian and 1 German individuals with Glycogen Storage Disease II (PMID: 30023291, 22676651) and has also been reported pathogenic by EGL in ClinVar (Variation ID: 194154). This variant has been identified in 0.062% (1/1620) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374470794). 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 provide some evidence that the p.Ser601Leu variant may impact GAA activity and protein levels (PMID: 22644586). 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. One additional variant at the the same position, p.Ser601Trp, has been curated likely pathogenic by our study, slightly supporting that a change at this position may not be tolerated (Variation ID: 501793; PMID: 17056254). The presence of this variant in combination with a reported pathogenic variant in an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Ser601Leu variant is pathogenic (PMID: 22676651). The phenotype of a compound heterozygous variant is highly specific for Glycogen Storage Disease II based on GAA activity assays with lymphocytes (PMID: 22676651). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Supporting, PM2, PM5_Supporting, PP3, PP4 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001242470 SCV001774623 pathogenic Glycogen storage disease, type II 2021-07-27 criteria provided, single submitter clinical testing Variant summary: GAA c.1802C>T (p.Ser601Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 150998 control chromosomes (gnomAD). c.1802C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) from different ethnicities (e.g. Chen_2017, Bali_2012, Herzog_2012, Monies_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused a significant decrease in protein levels and in enzymatic activity (Kroos_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity Omics RCV000174449 SCV002021181 pathogenic not provided 2023-09-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV001242470 SCV004195447 pathogenic Glycogen storage disease, type II 2023-10-16 criteria provided, single submitter clinical testing
Natera, Inc. RCV001242470 SCV002092062 pathogenic Glycogen storage disease, type II 2021-03-01 no assertion criteria provided clinical testing

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