Submissions for variant NM_001164277.2(SLC37A4):c.1243C>T (p.Arg415Ter)

gnomAD frequency: 0.00004  dbSNP: rs121908979

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196429	SCV001367037	pathogenic	Phosphate transport defect	2019-10-10	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007346	SCV001406760	pathogenic	Glucose-6-phosphate transport defect	2024-03-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg415*) in the SLC37A4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the SLC37A4 protein. This variant is present in population databases (rs121908979, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease 1b (PMID: 10482962, 10931421, 15059622, 21575371). This variant is also known as 1412C>T. ClinVar contains an entry for this variant (Variation ID: 6934). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the C-terminus of the SLC37A4 protein. Other variant(s) that disrupt this region (p.Lys426Glnfs*4) have been observed in individuals with SLC37A4-related conditions (PMID: 24385852). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007346	SCV001737804	pathogenic	Glucose-6-phosphate transport defect	2021-05-19	criteria provided, single submitter	clinical testing	Variant summary: SLC37A4 c.1243C>T (p.Arg415X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.4e-05 in 249028 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC37A4 causing Glycogen Storage Disease Type Ib (4.4e-05 vs 0.0012), allowing no conclusion about variant significance. c.1243C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type Ib (e.g. Veiga-da-Cunha_1999, Kojima_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496292	SCV002804222	likely pathogenic	Phosphate transport defect; Glucose-6-phosphate transport defect; Congenital disorder of glycosylation, type IIw	2022-04-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007346	SCV004202440	pathogenic	Glucose-6-phosphate transport defect	2024-02-25	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989281	SCV004806876	pathogenic	Congenital disorder of glycosylation, type IIw	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000007346	SCV000027544	pathogenic	Glucose-6-phosphate transport defect	1999-09-01	no assertion criteria provided	literature only