rs121909731

Positions:

• chr10-87057692-G-A
• chr10-87057692-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_005271.5(GLUD1):​c.1493C>T​(p.Ser498Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLUD1 NM_005271.5 missense, splice_region
• Scores: Splicing: ADA: 0.9471
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 9.60

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87057692-G-A is Pathogenic according to our data. Variant chr10-87057692-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16122.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.1493C>T	p.Ser498Leu	missense_variant, splice_region_variant	11/13	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5	c.1493C>T	p.Ser498Leu	missense_variant, splice_region_variant	11/13	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1370344 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 686750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

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

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperinsulinism-hyperammonemia syndrome Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 498 of the GLUD1 protein (p.Ser498Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLUD1-related conditions (PMID: 9571255, 23869231, 25008049, 26759084, 27188453, 28165182). In at least one individual the variant was observed to be de novo. This variant is also known as c.1506C>T (p.Ser445Leu). ClinVar contains an entry for this variant (Variation ID: 16122). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2019	DNA sequence analysis of the GLUD1 gene demonstrated a sequence change, c.1493C>T, in exon 11 that results in an amino acid change, p.Ser498Leu. This sequence change is absent from population databases such as ExAC and gnomAD, and it affects a moderately conserved amino acid residue located in a domain of the GLUD1 protein that is known to be functional. This sequence change has previously been identified in patients with hyperinsulinism-hyperammonemia syndrome (named as p.Ser445Leu) in the de-novo state (Stanley et al,1998). In the affected patients, glutamate dehydrogenase had reduced sensitivity to inhibition by GTP (Stanley et al,1998). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 09, 2023	The GLUD1 c.1493C>T (p.Ser498Leu) missense variant, which is also known as p.Ser445Leu, is located in the allosteric domain of glutamate dehydrogenase 1. Across a selection of the peer-reviewed literature, the variant has been reported in at least six unrelated individuals with hyperinsulinism-hyperammonemia syndrome, including in a de novo state (PMID: 9571255; 19046187; 19344873; 26759084; 28165182). Lymphoblasts from patients showed impaired inhibition of glutamate dehydrogenase by GTP. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the p.Ser498Leu variant may impact the gene or gene product, and functional studies in HEK293T cells have shown that this variant leads to a gain in enzyme function by reducing the sensitivity of glutamate dehydrogenase to inhibition by GTP (PMID: 28165182). This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1493C>T (p.Ser498Leu) variant is classified as pathogenic for hyperinsulinism-hyperammonemia syndrome. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1493C>T(p.Ser498Leu) in GLUD1 gene has been reported in the literature in individuals with GLUD1-related conditions and has been observed to be de novo in multiple individuals affected with GLUD1-related conditions (Sarajlija A et.al.,2016). This variant has been reported to the ClinVar database as Pathogenic. The p.Ser498Leu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ser at position 498 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ser498Leu in GLUD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro functional studies demonstrate reduced sensitivity to GTP inhibition (Barrosse-Antle et al., 2017); This variant is associated with the following publications: (PMID: 26759084, 28165182, 25008049, 9571255, 28135719, 31119523, 27188453, 10636977, 30306091, 30098243, 23869231, 26758964, 31785789) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.75
Sift	Benign	0.054	T
Sift4G	Benign	0.22	T
Polyphen		0.33	B
Vest4		0.50
MutPred		0.78		Loss of glycosylation at S498 (P = 0.0227);
MVP		0.95
MPC		1.1
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.61
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: rs121909731; hg19: chr10-88817449;