Submissions for variant NM_000642.3(AGL):c.2681+4dup

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000631162	SCV000752162	uncertain significance	Glycogen storage disease type III	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 20 of the AGL gene. It does not directly change the encoded amino acid sequence of the AGL protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs754242194, ExAC 0.002%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 17047887). This variant is also known as IVS21+5insA. 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 may disrupt the consensus splice site. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000631162	SCV002767899	uncertain significance	Glycogen storage disease type III	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease III (GSD III; MIM#232400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252- This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable non-canonical variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as a VUS in ClinVar, in two unaffected carriers (Invitae - via personal communication). In addition, it has been reported in a Turkish homozygote individual with GSD III (PMID: 17047887). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV000631162	SCV004050014	uncertain significance	Glycogen storage disease type III	2023-04-11	criteria provided, single submitter	clinical testing

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