rs9421572

Variant names:

• chr10-87061032-T-C
• rs9421572
• NM_005271.5:c.942A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-87061032-T-C
• chr10-87061032-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005271.5(GLUD1):​c.942A>G​(p.Leu314Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,134 control chromosomes in the GnomAD database, including 14,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1509 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13415 hom.)
• Consequence: GLUD1 NM_005271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.168
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism-hyperammonemia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-87061032-T-C is Benign according to our data. Variant chr10-87061032-T-C is described in ClinVar as Benign. ClinVar VariationId is 129164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.168 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	NM_005271.5	MANE Select	c.942A>G	p.Leu314Leu	synonymous	Exon 7 of 13	NP_005262.1
	GLUD1	NM_001318900.1		c.543A>G	p.Leu181Leu	synonymous	Exon 7 of 13	NP_001305829.1
	GLUD1	NM_001318901.1		c.441A>G	p.Leu147Leu	synonymous	Exon 10 of 16	NP_001305830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.942A>G	p.Leu314Leu	synonymous	Exon 7 of 13	ENSP00000277865.4
	GLUD1	ENST00000684338.1		c.942A>G	p.Leu314Leu	synonymous	Exon 7 of 13	ENSP00000507457.1
	GLUD1	ENST00000681988.1		c.441A>G	p.Leu147Leu	synonymous	Exon 9 of 15	ENSP00000507316.1

Frequencies

GnomAD3 genomes AF: 0.0938 AC: 14264 AN: 152078 Hom.: 1510 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.124 AC: 31252 AN: 251474 AF XY: 0.122

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0712

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.589

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0922

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.105 AC: 153756 AN: 1460938 Hom.: 13415 Cov.: 32 AF XY: 0.104 AC XY: 75703 AN XY: 726832

African (AFR) AF: 0.0164 AC: 550 AN: 33466

American (AMR) AF: 0.0761 AC: 3404 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3119 AN: 26124

East Asian (EAS) AF: 0.592 AC: 23469 AN: 39676

South Asian (SAS) AF: 0.0664 AC: 5724 AN: 86252

European-Finnish (FIN) AF: 0.146 AC: 7815 AN: 53420

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5766

European-Non Finnish (NFE) AF: 0.0919 AC: 102124 AN: 1111160

Other (OTH) AF: 0.121 AC: 7295 AN: 60352

GnomAD4 genome AF: 0.0938 AC: 14272 AN: 152196 Hom.: 1509 Cov.: 32 AF XY: 0.0983 AC XY: 7317 AN XY: 74398

African (AFR) AF: 0.0196 AC: 814 AN: 41544

American (AMR) AF: 0.0949 AC: 1450 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3472

East Asian (EAS) AF: 0.590 AC: 3056 AN: 5178

South Asian (SAS) AF: 0.0812 AC: 391 AN: 4818

European-Finnish (FIN) AF: 0.146 AC: 1545 AN: 10574

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6309 AN: 68008

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.0844 Hom.: 300

Bravo AF: 0.0905

Asia WGS AF: 0.290 AC: 1005 AN: 3478

EpiCase AF: 0.0870

EpiControl AF: 0.0904

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Oct 23, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Hyperinsulinism-hyperammonemia syndrome Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		0.17
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9421572; hg19: chr10-88820789; COSMIC: COSV53278976; COSMIC: COSV53278976;