1-93894707-C-T

Variant names:

• chr1-93894707-C-T
• NM_002061.4:c.562G>A

Variant summary

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

The NM_002061.4(GCLM):​c.562G>A​(p.Val188Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GCLM NM_002061.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

GCLM (HGNC:4312): (glutamate-cysteine ligase modifier 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. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

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=0.34738338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLM	NM_002061.4	c.562G>A	p.Val188Ile	missense_variant	Exon 6 of 7	ENST00000370238.8	NP_002052.1
GCLM	NM_001308253.2	c.496G>A	p.Val166Ile	missense_variant	Exon 5 of 6		NP_001295182.1
GCLM	XM_047418031.1	c.562G>A	p.Val188Ile	missense_variant	Exon 6 of 7		XP_047273987.1
GCLM	XM_011541261.3	c.298G>A	p.Val100Ile	missense_variant	Exon 6 of 7		XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLM	ENST00000370238.8	c.562G>A	p.Val188Ile	missense_variant	Exon 6 of 7	1	NM_002061.4	ENSP00000359258.3
GCLM	ENST00000615724.1	c.496G>A	p.Val166Ile	missense_variant	Exon 5 of 6	1		ENSP00000484507.1
GCLM	ENST00000467772.1	n.562G>A		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562G>A (p.V188I) alteration is located in exon 6 (coding exon 6) of the GCLM gene. This alteration results from a G to A substitution at nucleotide position 562, causing the valine (V) at amino acid position 188 to be replaced by an isoleucine (I). 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	0.24
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.17
Sift	Benign	0.12	T;.
Sift4G	Benign	0.13	T;T
Polyphen		0.79	P;.
Vest4		0.45
MutPred		0.54		Loss of disorder (P = 0.1761);.;
MVP		0.22
MPC		0.56
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.091
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-94360263;