ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.546+6C>T

gnomAD frequency: 0.00009  dbSNP: rs375727055
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000330299 SCV000336948 uncertain significance not provided 2015-11-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000818055 SCV000958649 uncertain significance Glycogen storage disease, type II 2022-09-27 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs375727055, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 284357). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab RCV000818055 SCV002027222 uncertain significance Glycogen storage disease, type II 2021-09-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000818055 SCV002794507 uncertain significance Glycogen storage disease, type II 2021-09-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323491 SCV004030050 uncertain significance not specified 2023-07-21 criteria provided, single submitter clinical testing Variant summary: GAA c.546+6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict either no significant impact on normal splicing or strengthening of the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.6e-05 in 235214 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.546+6C>T in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000818055 SCV002091932 uncertain significance Glycogen storage disease, type II 2019-10-28 no assertion criteria provided clinical testing

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