ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2155G>T (p.Ala719Ser)

dbSNP: rs143324027
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000675240 SCV000339871 uncertain significance not provided 2016-03-03 criteria provided, single submitter clinical testing
Invitae RCV000631086 SCV000752079 likely benign Glycogen storage disease, type II 2024-01-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375522 SCV001572377 uncertain significance not specified 2021-04-05 criteria provided, single submitter clinical testing Variant summary: GAA c.2155G>T (p.Ala719Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 218544 control chromosomes (gnomAD v2.1.1). Furthermore, the variant allele was found at a frequency of 0.0001906 in 152186 control chromosomes in the gnomAD v3.1.1 database, including 1 homozygote. These frequencies are not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease), allowing no conclusion about variant significance. c.2155G>T has been reported in the literature as a single heterozygous occurrence (i.e. no other GAA variants identified) in an individual with a limb girdle-like muscular pattern with persistent hyperCKaemia who exhibited reduced GAA muscle activity. The authors concluded that no GAA pathogenic mutations were detected in their study while their data suggested that reduced GAA activity may occur in any condition of impaired autophagy (Napolitano_2021). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV000675240 SCV001805563 uncertain significance not provided 2019-10-28 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Genome-Nilou Lab RCV000631086 SCV001810177 uncertain significance Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000631086 SCV002768220 uncertain significance Glycogen storage disease, type II 2020-07-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with [disease]. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2.1.1) <0.01 for a recessive condition. 0.000244 (61 heterozygotes, 0 homozygotes). (SP) 0309 – Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2.1.1) p.(Ala719Glu): 0.000149 (37 heterozygotes, 0 homozygotes). p.(Ala719Thr): 0.000244 (7 heterozygotes, 0 homozygotes). p.(Ala719Val): 0.000009 (2 heterozygotes, 0 homozygotes). (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. Conflicting evidence depending on source. It may be located within a catalytic domain, glycosyl hydrolase family 31 (DECIPHER, PMID: 30281819). (I) 0710 – Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Ala719Glu): ClinVar: VUS x4. p.(Ala719Thr): ClinVar: VUS x2. p.(Ala719Val): ClinVar: VUS x1. At VCGS, p.(Ala719Glu) has also been previously observed once in our HCM patient cohort. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: Conflicting interpretations of pathogenicity: 2x VUS + 1x Likely benign (most recent). PMID: 30281819: computational analysis only by multiple in silico programs predicts this variant has a neutral effect on the protein. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign
CeGaT Center for Human Genetics Tuebingen RCV000675240 SCV002822431 likely benign not provided 2023-04-01 criteria provided, single submitter clinical testing GAA: BP4, BS2
Revvity Omics, Revvity Omics RCV000675240 SCV003828515 uncertain significance not provided 2023-08-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000675240 SCV000800886 uncertain significance not provided 2017-05-17 no assertion criteria provided clinical testing

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