Submissions for variant NM_001164277.2(SLC37A4):c.547T>C (p.Cys183Arg)

dbSNP: rs193302893

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824595	SCV002074403	pathogenic	Glucose-6-phosphate transport defect	2022-01-22	criteria provided, single submitter	clinical testing	Variant summary: SLC37A4 c.547T>C, legacy nucleotide naming as T716C in exon 3 (p.Cys183Arg) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Two of two in-silico tools predict a damaging effect of the variant on protein function while three in-silico tools did not provide a prediction. The variant allele was found at a frequency of 4.2e-06 in 240882 control chromosomes. c.547T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disease Type Ib (example, Veiga-da-Cunha_1999, Galli_1999, Hiraiwa_1999, Janecke_2000, Sperb-Ludwig_2019). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Hiraiwa_1999, Chen_2002). The most pronounced variant effect results in a complete disruption of microsomal glucose-6-phosphate (G6P) uptake resulting from defective transport. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001824595	SCV002247385	pathogenic	Glucose-6-phosphate transport defect	2023-01-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 68284). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 12444104, 18835800). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC37A4 protein function. This variant is also known as T716C, c.716T>C. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 10482962, 10518030, 15906092, 16435186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs193302893, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 183 of the SLC37A4 protein (p.Cys183Arg).
UniProtKB/Swiss-Prot	RCV000059135	SCV000090664	not provided	not provided		no assertion provided	not provided