6-53498947-T-C

Variant names:

• chr6-53498947-T-C
• NM_001498.4:c.1723A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001498.4(GCLC):​c.1723A>G​(p.Arg575Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCLC NM_001498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34116358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1723A>G	p.Arg575Gly	missense_variant	Exon 16 of 16	ENST00000650454.1	NP_001489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1723A>G	p.Arg575Gly	missense_variant	Exon 16 of 16		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1723A>G (p.R575G) alteration is located in exon 16 (coding exon 16) of the GCLC gene. This alteration results from a A to G substitution at nucleotide position 1723, causing the arginine (R) at amino acid position 575 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Uncertain	0.47	.;T;T;T;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	.;L;L;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	.;.;N;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.28	.;.;T;.;.;.
Sift4G	Benign	0.37	.;.;T;.;.;.
Polyphen		0.38	.;B;B;.;.;.
Vest4		0.38
MutPred		0.51		.;Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);.;.;.;
MVP		0.63
MPC		0.78
ClinPred		0.22	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-53363745;