1-182384555-GCG-ACA

Variant names:

• chr1-182384555-GCG-ACA
• NM_001033044.4:c.970_972delCGCinsTGT
• GLUL p.Arg324Cys

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM5 PP3

The NM_001033044.4(GLUL):​c.970_972delCGCinsTGT​(p.Arg324Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLUL NM_001033044.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 0 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy 116

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• PS1: Transcript NM_001033044.4 (GLUL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUL	NM_001033044.4	MANE Select	c.970_972delCGCinsTGT	p.Arg324Cys	missense	N/A	NP_001028216.1	P15104
	GLUL	NM_001033056.4		c.970_972delCGCinsTGT	p.Arg324Cys	missense	N/A	NP_001028228.1	P15104
	GLUL	NM_002065.7		c.970_972delCGCinsTGT	p.Arg324Cys	missense	N/A	NP_002056.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUL	ENST00000331872.11	TSL:1 MANE Select	c.970_972delCGCinsTGT	p.Arg324Cys	missense	N/A	ENSP00000356537.6	P15104
	GLUL	ENST00000339526.9	TSL:1	c.1372_1374delCGCinsTGT	p.Arg458Cys	missense	N/A	ENSP00000344958.5	A0ABJ7BD24
	GLUL	ENST00000311223.9	TSL:1	c.970_972delCGCinsTGT	p.Arg324Cys	missense	N/A	ENSP00000307900.5	P15104

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-182353690;