rs193302893
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001164278.2(SLC37A4):c.547T>C(p.Cys183Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,554 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 (★★).
Frequency
Consequence
NM_001164278.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164278.2 | c.547T>C | p.Cys183Arg | missense_variant | Exon 6 of 12 | NP_001157750.1 | ||
SLC37A4 | NM_001164277.2 | c.547T>C | p.Cys183Arg | missense_variant | Exon 6 of 11 | NP_001157749.1 | ||
SLC37A4 | NM_001164280.2 | c.547T>C | p.Cys183Arg | missense_variant | Exon 4 of 9 | NP_001157752.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240882Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130680
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461554Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727042
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Glucose-6-phosphate transport defect Pathogenic:2
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. -
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). This variant is present in population databases (rs193302893, gnomAD 0.0009%). 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 also known as T716C, c.716T>C. ClinVar contains an entry for this variant (Variation ID: 68284). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -
Congenital disorder of glycosylation, type IIw Pathogenic:1
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not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at