rs56275071

Positions:

• chr10-87062757-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_005271.5(GLUD1):​c.820C>T​(p.Arg274Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLUD1 NM_005271.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.11

Genes affected

GLUD1 (HGNC:4335): (glutamate dehydrogenase 1) This gene encodes glutamate dehydrogenase, which is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid-induced insulin secretion. It is allosterically activated by ADP and inhibited by GTP and ATP. Activating mutations in this gene are a common cause of congenital hyperinsulinism. Alternative splicing of this gene results in multiple transcript variants. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Related pseudogenes have been identified on chromosomes 10, 18 and X. [provided by RefSeq, Jan 2016]

GLUD1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 10-87062757-G-A is Pathogenic according to our data. Variant chr10-87062757-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.820C>T	p.Arg274Cys	missense_variant	6/13	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5	c.820C>T	p.Arg274Cys	missense_variant	6/13	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperinsulinism-hyperammonemia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	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). 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 GLUD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 09, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.90		Loss of methylation at R274 (P = 0.0037);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56275071; hg19: chr10-88822514;