Submissions for variant NM_001164277.2(SLC37A4):c.1099G>A (p.Ala367Thr)

gnomAD frequency: 0.00002  dbSNP: rs80356492

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000059118	SCV000331845	uncertain significance	not provided	2017-02-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000288403	SCV000933754	likely pathogenic	Glucose-6-phosphate transport defect	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 367 of the SLC37A4 protein (p.Ala367Thr). This variant is present in population databases (rs80356492, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive glycogen storage disease (PMID: 10518030, 10923042, 32300528). This variant is also known as c.1268G>A. ClinVar contains an entry for this variant (Variation ID: 21298). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 12444104, 18835800). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000288403	SCV002060353	likely pathogenic	Glucose-6-phosphate transport defect	2021-11-01	criteria provided, single submitter	clinical testing	NM_001164277.1(SLC37A4):c.1099G>A(A367T) is a missense variant classified as likely pathogenic in the context of glycogen storage disease type Ib. A367T has been observed in cases with relevant disease (PMID: 15669677, 15906092, 10923042, 32300528, Savostyanov_2017_(no PMID; article), Odlotilova_2013_(no PMID; thesis)). Functional assessments of this variant are available in the literature (PMID: 12444104, 18835800, 21983240). A367T has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, NM_001164277.1(SLC37A4):c.1099G>A(A367T) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000288403	SCV003800869	likely pathogenic	Glucose-6-phosphate transport defect	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: SLC37A4 c.1099G>A (p.Ala367Thr) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 248140 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC37A4 causing Glycogen Storage Disease Type Ib (5.6e-05 vs 0.0012), allowing no conclusion about variant significance. c.1099G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease Type Ib (example, Galli_1999, Santer_2000, Trioche_2004, Melis_2005, Wicker_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 23% of normal Microsomal G6P uptake activity in vitro (example, Chen_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000288403	SCV004202443	pathogenic	Glucose-6-phosphate transport defect	2024-03-19	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059118	SCV000090647	not provided	not provided		no assertion provided	not provided