Submissions for variant NM_001164277.2(SLC37A4):c.1124+1G>C

dbSNP: rs782630676

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707348	SCV000836440	pathogenic	Glucose-6-phosphate transport defect	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the SLC37A4 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive SLC37A4-related conditions and/or glycogen storage disease type I (PMID: 10482875, 11071391, 16716283; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8+1G>C. ClinVar contains an entry for this variant (Variation ID: 583102). 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. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000707348	SCV002557749	pathogenic	Glucose-6-phosphate transport defect	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease type Ib (GSD Ib) (MIM#232220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other canonical splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Four different variants in the same splice junction have previously been reported, sometimes in an alternate transcript using different nomenclature, in at least five individuals with GSD Ib (MIM#232220) (HGMD, PMIDs: 10482875, 11071391, 15906092, 33977030). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in a compound heterozygous state, sometimes in an alternate transcript using different nomenclature, in three individuals with GSD Ib (MIM#232220) (HGMD, PMIDs: 16716283, 25881301, 29549044). (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) 1206 - This variant has been shown to be paternally inherited (external testing by Invitae). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign