rs121909737

Positions:

• chr10-87061009-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLUD1 NM_005271.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_005271.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 10-87061009-C-T is Pathogenic according to our data. Variant chr10-87061009-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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: 1 AN: 1461492 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely 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	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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.022	D
Polyphen		0.38	B
Vest4		0.84
MutPred		0.84		Loss of MoRF binding (P = 0.0314);
MVP		0.97
MPC		1.5
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.60
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs121909737; hg19: chr10-88820766;