ClinVar

Description

Variant summary: SLC37A4 c.148G>A (p.Gly50Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. As the variant alters a conserved last nucleotide of exon 3 adjacent to the intronic splicing donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. One predicts the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 152240 control chromosomes (gnomAD v4.0). c.148G>A has been reported in the literature in at-least one individual affected with Glycogen Storage Disease Type Ib (example, Choi_2017) although a different nucleotide change at the same location resulting in the same amino acid change has been reported among the pathogenic spectrum of variants in the SLC37A4 gene. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, however, the c.148G>C variant that results in the same amino acid change (p.Gly50Arg), abolishes the microsomal G6P uptake activity, and compromises G6PT stability (cited in Choi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30956637, 28224773). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.