rs193302892
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The ENST00000330775.9(SLC37A4):c.446G>A(p.Gly149Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,457,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G149G) has been classified as Likely benign.
Frequency
Consequence
ENST00000330775.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164277.2 | c.446G>A | p.Gly149Glu | missense_variant | 5/11 | ENST00000642844.3 | |
SLC37A4 | NM_001164279.2 | c.227G>A | p.Gly76Glu | missense_variant | 5/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC37A4 | ENST00000330775.9 | c.446G>A | p.Gly149Glu | missense_variant | 4/10 | 5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000292 AC: 7AN: 239678Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 130058
GnomAD4 exome AF: 0.00000892 AC: 13AN: 1457168Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3AN XY: 724498
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Glucose-6-phosphate transport defect Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 20, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 24, 2020 | Variant summary: SLC37A4 c.446G>A (p.Gly149Glu) results in a non-conservative amino acid change located in the Glycerate/sugar phosphate transporter, conserved signature motif (IPR021159) of the encoded protein sequence. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 239678 control chromosomes (gnomAD). The variant, c.446G>A, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Glycogen Storage Disease Type Ib (e.g. Hiraiwa_1999, Galli_1999, Lam_2000, Sperb-Ludwig_2019). These data indicate that the variant is likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant almost completely abolishes the glucose-6-phosphate transport activity of the protein (e.g. Hiraiwa_1999, Chen_2002, Chen_2008). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 149 of the SLC37A4 protein (p.Gly149Glu). This variant is present in population databases (rs193302892, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive glycogen storage disease type Ib (PMID: 10026167, 10518030, 12444104, 29581464). ClinVar contains an entry for this variant (Variation ID: 68280). 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 not expected to disrupt SLC37A4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 10026167, 12444104). For these reasons, this variant has been classified as Pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at