chr1-182384557-G-T

Variant names:

• chr1-182384557-G-T
• rs80358214
• NM_001033044.4:c.970C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The ENST00000331872.11(GLUL):​c.970C>A​(p.Arg324Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R324C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLUL ENST00000331872.11 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.54
• Publications: 21 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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-182384557-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16083.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 1-182384557-G-T is Pathogenic according to our data. Variant chr1-182384557-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29734.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000331872.11. 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.970C>A	p.Arg324Ser	missense	Exon 7 of 7	NP_001028216.1
	GLUL	NM_001033056.4		c.970C>A	p.Arg324Ser	missense	Exon 7 of 7	NP_001028228.1
	GLUL	NM_002065.7		c.970C>A	p.Arg324Ser	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.970C>A	p.Arg324Ser	missense	Exon 7 of 7	ENSP00000356537.6
	GLUL	ENST00000339526.9	TSL:1	c.1372C>A	p.Arg458Ser	missense	Exon 7 of 7	ENSP00000344958.5
	GLUL	ENST00000311223.9	TSL:1	c.970C>A	p.Arg324Ser	missense	Exon 8 of 8	ENSP00000307900.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Benign	0.049	D
Sift4G	Uncertain	0.014	D
Polyphen		0.95	P
Vest4		0.98
MutPred		0.91		Loss of MoRF binding (P = 0.0163)
MVP		0.96
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	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: rs80358214; hg19: chr1-182353692;