rs121907946

Positions:

• chr6-53507001-T-A
• chr6-53507001-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001498.4(GCLC):​c.1109A>T​(p.His370Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCLC NM_001498.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86

Genes affected

GCLC (HGNC:4311): (glutamate-cysteine ligase catalytic subunit) Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate-limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. This locus encodes the catalytic subunit, while the regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Mutations at this locus have been associated with hemolytic anemia due to deficiency of gamma-glutamylcysteine synthetase and susceptibility to myocardial infarction.[provided by RefSeq, Oct 2010]

GCLC-AS1 (HGNC:56649): (GCLC antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 6-53507001-T-A is Pathogenic according to our data. Variant chr6-53507001-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 3958.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1109A>T	p.His370Leu	missense_variant	10/16	ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.995A>T	p.His332Leu	missense_variant	9/15		NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1109A>T	p.His370Leu	missense_variant	10/16		NM_001498.4	ENSP00000497574	P1
GCLC-AS1	ENST00000655377.1	n.696T>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456938 Hom.: 0 Cov.: 27 AF XY: 0.00000276 AC XY: 2 AN XY: 725212

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gamma-glutamylcysteine synthetase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	.;D;D;T;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.0	.;M;M;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-11	.;.;D;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;.
Polyphen		1.0	.;D;D;.;.;.
Vest4		0.98
MutPred		0.96		.;Gain of stability (P = 0.1152);Gain of stability (P = 0.1152);.;.;.;
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.91

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: rs121907946; hg19: chr6-53371799;