20-34942488-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000178.4(GSS):c.491G>A(p.Arg164Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000787 in 1,613,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

GSS
NM_000178.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.99

Publications

10 publications found

Variant links:

Genes affected

GSS (HGNC:4624): (glutathione synthetase) Glutathione is important for a variety of biological functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport. The protein encoded by this gene functions as a homodimer to catalyze the second step of glutathione biosynthesis, which is the ATP-dependent conversion of gamma-L-glutamyl-L-cysteine to glutathione. Defects in this gene are a cause of glutathione synthetase deficiency. [provided by RefSeq, Jul 2008]

GSS Gene-Disease associations (from GenCC):

inherited glutathione synthetase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
glutathione synthetase deficiency with 5-oxoprolinuria
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

GSS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 20-34942488-C-T is Pathogenic according to our data. Variant chr20-34942488-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4 link	c.491G>A	p.Arg164Gln	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000651619.1	NP_000169.1	P48637-1V9HWJ1
GSS	NM_001322494.1 link	c.491G>A	p.Arg164Gln	missense_variant, splice_region_variant	Exon 5 of 13		NP_001309423.1	P48637-1V9HWJ1
GSS	NM_001322495.1 link	c.491G>A	p.Arg164Gln	missense_variant, splice_region_variant	Exon 5 of 13		NP_001309424.1	P48637-1V9HWJ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1 link	c.491G>A	p.Arg164Gln	missense_variant, splice_region_variant	Exon 5 of 13		NM_000178.4	ENSP00000498303.1		P48637-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000321

AC:

AN:

249356

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461016

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.0000998

AC:

111

AN:

1111710

Other (OTH)

AF:

0.000133

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000768

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutathione synthetase deficiency with 5-oxoprolinuria

Pathogenic:3

Nov 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 04, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GSS c.491G>A (p.Arg164Gln) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 3.2e-05 in 249356 control chromosomes. The variant of interest was observed in multiple affected individuals via publications in a homozygous or compound heterozygous state. GSS activity in these patients were significantly decreased (Shi_1996 and Njalsson_2005). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. ClinVar contains an entry for this variant (Variation ID: 8525). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 164 of the GSS protein (p.Arg164Gln). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121909307, gnomAD 0.006%). This missense change has been observed in individual(s) with gluthathione synthetase deficiency (PMID: 8896573, 15717202, 25851806, 28822442). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8525). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects GSS function (PMID: 8896573). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Aug 23, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.491G>A (p.R164Q) alteration is located in exon 5 (coding exon 4) of the GSS gene. This alteration results from a G to A substitution at nucleotide position 491, causing the arginine (R) at amino acid position 164 to be replaced by a glutamine (Q). However, this change occurs in the last base pair of coding exon4, which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (10/280724) total alleles studied. The highest observed frequency was 0.01% (8/127900) of European (non-Finnish) alleles. This variant has been detected as compound heterozygous and homozygous in multiple unrelated individuals with glutathione synthetase deficiency (Shi, 1996; Tokatli, 2007; Li, 2015). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense alteration, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Apr 05, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies using complementation assays demonstrate a damaging effect (Shi et al., 1996); Predicted to destroy the natural spice donor site for intron 5 with skipping of exon 5 (Shi et al., 1996); This variant is associated with the following publications: (PMID: 11445798, 28822442, 17479648, 26669244, 15717202, 25851806, 8896573, 25525159) -

Inherited glutathione synthetase deficiency

Pathogenic:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GSS c.491G>A (p.Arg164Gln) variant has been reported in three studies in individuals with 5-oxoprolinuria (a marker for glutathione synthetase deficiency), including two in a homozygous state, three in a compound heterozygous state with either another missense variant or a deletion variant, and in one heterozygote in whom the second variant was not identified (Shi et al. 1996; Tokatli et al. 2007; Li et al. 2015). The c.491G>A (p.Arg164Gln) variant was absent from 25 controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on two alleles only in a region of good sequence coverage so the variant is presumed to be rare. Functional studies in individual fibroblasts and erythrocytes demonstrated that the variant resulted in a defect in splicing and enzyme activity of only 5% of normal levels. Expression of p.Arg164Gln variant cDNAs in both yeast and E. coli showed no detectable GSS activity and a failure to complement growth in yeast (Shi et al. 1996; Tokatli et al. 2007). Based on the collective evidence, the p.Arg164Gln variant is classified as pathogenic for glutathione synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;D;D

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

.;D;.;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.5

L;.;L;L

PhyloP100

5.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

N;.;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.093

T;.;.;.

Sift4G

Benign

0.22

T;.;.;.

Polyphen

0.96

D;.;D;D

Vest4

0.40

MutPred

0.58

Loss of MoRF binding (P = 0.0248);Loss of MoRF binding (P = 0.0248);Loss of MoRF binding (P = 0.0248);Loss of MoRF binding (P = 0.0248);

MVP

0.91

MPC

0.29

ClinPred

0.44

GERP RS

3.8

PromoterAI

-0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.20

gMVP

0.76

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.72

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over