rs759518659
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM5PM2_SupportingPP4_ModeratePM3_StrongPS3_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1978C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 660 (p.Arg660Cys). At least 6 patients with clinical features consistent with Pompe disease have been reported with this variant; three with documented laboratory data showing deficiency of GAA in dried blood spot, or lymphocytes and muscle (PMID:17056254, 31193175, clinical laboratory data), and two reported to have deficient GAA activity and to be on enzyme replacement therapy on enzyme replacement therapy (PMID:25626711, 29122469, 31904026) (PP4_Moderate). Three of these patients are compound heterozygous, phase unknown, for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, either c.784G>A (p.Glu262Lys) (PMID 31193175), c.1082C>T (p.Pro361Leu) (clinical laboratory data), or c.546G>T (PMID:29124014) and another patient is homozygous (PMID:25626711) (PM3_Strong). An additional two patients are compound heterozygous for the variant and [c.1477C>T; c.2221G>A] ([p.Pro493Ser; p.Asp741Asn)] (PMID:29122469, 31904026), or c.1397T>G (p.Val466Gly) (PMID:17056254). The allelic data from the latter 2 patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/18006 alleles) in the East Asian 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, the variant results in <2% normal GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.966 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at this amino acid position, c.1979G>A (p.Arg660His) has been classified as pathogenic by the ClinGen LSD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 558604; 2 star review status) with four submitters classifying the variant as pathogenic, and two as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM5, PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815561/MONDO:0009290/010
Frequency
Consequence
ENST00000302262.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1978C>T | p.Arg660Cys | missense_variant | 14/20 | ENST00000302262.8 | NP_000143.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1978C>T | p.Arg660Cys | missense_variant | 14/20 | 1 | NM_000152.5 | ENSP00000305692 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000414 AC: 1AN: 241412Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131434
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1457932Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725038
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 660 of the GAA protein (p.Arg660Cys). 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 individual(s) with Pompe disease (PMID: 17056254, 29122469, 29124014, 31439017). ClinVar contains an entry for this variant (Variation ID: 558604). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). This variant disrupts the p.Arg660 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14643388, 20472203, 21484825, 22521436, 22555271, 27649523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 14, 2020 | The p.Arg660Cys variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29122469, 29124014, 17056254) and has been identified in 0.006% (1/18006) of East Asian chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759518659). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported on ClinVar as Likely Pathogenic by Counsyl and Pathogenic by Integrated Genetics (VariationID: 558604). In vitro functional studies using COS-7 cells transfected with the variant provide some evidence that the p.Arg660Cys variant may impact protein function (PMID: 19862843). 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 pathogenic variant, resulting in a different amino acid change at the same position, p.Arg660His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 14643388, 19862843, 22658377, 20638881, 20472203, 21484825; Variation ID: 189172). Additionally, this variant has been reported in combination with likely pathogenic variant p.Val466Gly and in an individual with glycogen storage disease II (PMID: 17056254). The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on reduced GAA activity in lymphocytes and muscle tissue from affected individuals (PMID: 17056254, 29124014). 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 studies demonstrating an impact on protein function and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PP4 (Richards 2015). - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Mar 01, 2022 | The NM_000152.5:c.1978C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 660 (p.Arg660Cys). At least 6 patients with clinical features consistent with Pompe disease have been reported with this variant; three with documented laboratory data showing deficiency of GAA in dried blood spot, or lymphocytes and muscle (PMID: 17056254, 31193175, clinical laboratory data), and two reported to have deficient GAA activity and to be on enzyme replacement therapy on enzyme replacement therapy (PMID: 25626711, 29122469, 31904026) (PP4_Moderate). Three of these patients are compound heterozygous, phase unknown, for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, either c.784G>A (p.Glu262Lys) (PMID 31193175), c.1082C>T (p.Pro361Leu) (clinical laboratory data), or c.546G>T (PMID: 29124014) and another patient is homozygous (PMID: 25626711) (PM3_Strong). An additional two patients are compound heterozygous for the variant and [c.1477C>T; c.2221G>A] ([p.Pro493Ser; p.Asp741Asn)] (PMID: 29122469, 31904026), or c.1397T>G (p.Val466Gly) (PMID: 17056254). The allelic data from the latter 2 patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/18006 alleles) in the East Asian 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, the variant results in <2% normal GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.966 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at this amino acid position, c.1979G>A (p.Arg660His) has been classified as pathogenic by the ClinGen LSD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 558604; 2 star review status) with four submitters classifying the variant as pathogenic, and two as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM5, PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting. (Approved by LSD VCEP on Feb 15, 2022). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2018 | Variant summary: GAA c.1978C>T (p.Arg660Cys) results in a non-conservative amino acid change located in the Catalytic GH31 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity, potentially, due to the change affecting maturation process (Flanagan_2009; Palmer_2007). The variant allele was found at a frequency of 1.1e-05 in 1/91962 control chromosomes in ExAC dataset. The c.1978C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. In addition, another alteration of the same codon, R660H, has been reported as "Pathogenic" for Pompe disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 19, 2020 | PS3, PM2, PM5, PS4_M, PP3, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 10, 2022 | - - |
GAA-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 14, 2024 | The GAA c.1978C>T variant is predicted to result in the amino acid substitution p.Arg660Cys. This variant has been reported in the homozygous state or along with a second GAA variant in patients with glycogen storage disease type 2 (GSD II), also known as Pompe disease (Palmer et al. 2007. PubMed ID: 17056254; Hahn et al. 2015. PubMed ID: 25626711; Mori et al. 2017. PubMed ID: 29122469; Desai et al. 2019. PubMed ID: 31193175). In a functional study using COS-7 cells, the p.Arg660Cys substitution was reported to reduce GAA activity to <2% relative to control (Flanagan et al. 2009. PubMed ID: 19862843). A different missense variant impacting the same amino acid (c.1979G>A, p.Arg660His) has been interpreted as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (LSD VCEP) (https://www.ncbi.nlm.nih.gov/clinvar/variation/189172). The c.1978C>T (p.Arg660Cys) variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. It has also been interpreted as pathogenic by the ClinGen LSD VCEP, as well as pathogenic or likely pathogenic by other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/558604). Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at