rs80358215

Variant names:

• chr1-182384506-G-A
• rs80358215
• NM_001033044.4:c.1021C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001033044.4(GLUL):​c.1021C>T​(p.Arg341Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R341H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GLUL NM_001033044.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56
• Publications: 16 publications found

Genes affected

GLUL (HGNC:4341): (glutamate-ammonia ligase) The protein encoded by this gene belongs to the glutamine synthetase family. It catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. This protein plays a role in ammonia and glutamate detoxification, acid-base homeostasis, cell signaling, and cell proliferation. Glutamine is an abundant amino acid, and is important to the biosynthesis of several amino acids, pyrimidines, and purines. Mutations in this gene are associated with congenital glutamine deficiency, and overexpression of this gene was observed in some primary liver cancer samples. There are six pseudogenes of this gene found on chromosomes 2, 5, 9, 11, and 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

GLUL Gene-Disease associations (from GenCC):

• congenital brain dysgenesis due to glutamine synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• developmental and epileptic encephalopathy 116

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 1-182384506-G-A is Pathogenic according to our data. Variant chr1-182384506-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16084.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033044.4. 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
	GLUL	NM_001033044.4	MANE Select	c.1021C>T	p.Arg341Cys	missense	Exon 7 of 7	NP_001028216.1
	GLUL	NM_001033056.4		c.1021C>T	p.Arg341Cys	missense	Exon 7 of 7	NP_001028228.1
	GLUL	NM_002065.7		c.1021C>T	p.Arg341Cys	missense	Exon 8 of 8	NP_002056.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUL	ENST00000331872.11	TSL:1 MANE Select	c.1021C>T	p.Arg341Cys	missense	Exon 7 of 7	ENSP00000356537.6
	GLUL	ENST00000339526.9	TSL:1	c.1423C>T	p.Arg475Cys	missense	Exon 7 of 7	ENSP00000344958.5
	GLUL	ENST00000311223.9	TSL:1	c.1021C>T	p.Arg341Cys	missense	Exon 8 of 8	ENSP00000307900.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727178

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111846

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital brain dysgenesis due to glutamine synthetase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.54
MutPred		0.92		Loss of disorder (P = 0.0302)
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.85
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80358215; hg19: chr1-182353641; COSMIC: COSV59381541; COSMIC: COSV59381541;