rs121909737
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005271.5(GLUD1):c.965G>A(p.Arg322His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,492 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLUD1 | NM_005271.5 | c.965G>A | p.Arg322His | missense_variant | 7/13 | ENST00000277865.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLUD1 | ENST00000277865.5 | c.965G>A | p.Arg322His | missense_variant | 7/13 | 1 | NM_005271.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461492Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727098
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hyperinsulinism-hyperammonemia syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 27, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jun 23, 2023 | A heterozygous variation in exon 7 of the GLUD1 gene that results in the amino acid substitution of Histidine for arginine at codon 322 was detected. The observed variant c.965G>A (p.Arg322His) has not been reported in the 1000 genomes databases. The in silico prediction of the variant are possibly damaging by LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2022 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 GLUD1 protein function. ClinVar contains an entry for this variant (Variation ID: 16129). This variant is also known as R269H. This missense change has been observed in individual(s) with hyperinsulinism hyperammonemia syndrome (PMID: 11214910, 27188453, 30306091). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 322 of the GLUD1 protein (p.Arg322His). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at