ClinVar Miner

Submissions for variant NM_005271.5(GLUD1):c.820C>T (p.Arg274Cys)

dbSNP: rs56275071
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000017508 SCV001414509 pathogenic Hyperinsulinism-hyperammonemia syndrome 2024-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 274 of the GLUD1 protein (p.Arg274Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with HI/HA (PMID: 11214910, 26759084, 27188453, 30306091, 30425915). It has also been observed to segregate with disease in related individuals. This variant is also known as c.833C>T (p.Arg221Cys). ClinVar contains an entry for this variant (Variation ID: 16128). 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 GLUD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV001818165 SCV002072086 pathogenic not provided 2020-11-09 criteria provided, single submitter clinical testing DNA sequence analysis of the GLUD1 gene demonstrated a sequence change, c.820C>T, in exon 6 that results in an amino acid change, p.Arg274Cys. This sequence change does not appear to have been previously described in patients with GLUD1-related disorders and has also not been described in the large population databases such as ExAC and gnomAD (dbSNP rs56275071). This sequence change has been described in patients with hyperinsulinism-hyperammonemia who presented with recurrent episodes of hypoglycemia and seizures (PMIDs: 31119523, 30425915). It has also been described segregating with the disease phenotype in a family (PMID: 11214910). The p.Arg274Cys change affects a highly conserved amino acid residue located in a domain of the GLUD1 protein that is known to be functional. The p.Arg274Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Fulgent Genetics, Fulgent Genetics RCV000017508 SCV002810981 pathogenic Hyperinsulinism-hyperammonemia syndrome 2022-04-21 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000017508 SCV005400893 pathogenic Hyperinsulinism-hyperammonemia syndrome 2023-06-22 criteria provided, single submitter clinical testing The missense variant c.820C>T (p.Arg274Cys) in the GLUD1 gene has been reported previously in heterozygous state in individuals affected with Hyperinsulinism-hyperammonemia Syndrome. This sequence change has been described in patients with hyperinsulinism-hyperammonemia who presented with recurrent episodes of hypoglycemia, epileptic seizures and mild mental retardation (Strajnar et al., 2018; Roy et al., 2019). The p.Arg274Cys change affects a highly conserved amino acid residue located in a domain of the GLUD1 protein that is known to be functional (Boodhansingh et al., 2022; Santer et al., 2001). It is submitted to ClinVar as Pathogenic (multiple submitters). The variant is absent in the gnomAD Exomes. The amino acid Arg at position 274 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017508 SCV000037780 pathogenic Hyperinsulinism-hyperammonemia syndrome 2001-01-01 no assertion criteria provided literature only

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