rs1169592069

chr10-87057743-T-Achr10-87057743-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005271.5(GLUD1):c.1442A>T(p.His481Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,446,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GLUD1 NM_005271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2747564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLUD1	NM_005271.5	c.1442A>T	p.His481Leu	missense_variant	11/13	ENST00000277865.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLUD1	ENST00000277865.5	c.1442A>T	p.His481Leu	missense_variant	11/13	1	NM_005271.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446148 Hom.: 0 Cov.: 27 AF XY: 0.00000555 AC XY: 4 AN XY: 720446

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: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperinsulinism-hyperammonemia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GLUD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with leucine at codon 481 of the GLUD1 protein (p.His481Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	23
Dann	Benign	0.94
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.076	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.45
Sift	Benign	0.57	T
Sift4G	Benign	0.79	T
Polyphen		0.0010	B
Vest4		0.47
MutPred		0.42		Loss of methylation at K477 (P = 0.0472);
MVP		0.94
MPC		1.4
ClinPred		0.36	T
GERP RS		5.0
Varity_R		0.39
gMVP		0.71

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: rs1169592069; hg19: chr10-88817500;