rs28936396

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_000178.4(GSS):c.373C>T(p.Arg125Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

GSS
NM_000178.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.91

Publications

7 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 12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-34942605-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2736963.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 20-34942606-G-A is Pathogenic according to our data. Variant chr20-34942606-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GSS	NM_000178.4 link	c.373C>T	p.Arg125Cys	missense_variant	Exon 5 of 13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1 link	c.373C>T	p.Arg125Cys	missense_variant	Exon 5 of 13		NP_001309423.1
GSS	NM_001322495.1 link	c.373C>T	p.Arg125Cys	missense_variant	Exon 5 of 13		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1 link	c.373C>T	p.Arg125Cys	missense_variant	Exon 5 of 13		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251436

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111960

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000243

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.000845

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000903

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutathione synthetase deficiency with 5-oxoprolinuria

Pathogenic:3

Jan 31, 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 cysteine, which is neutral and slightly polar, at codon 125 of the GSS protein (p.Arg125Cys). This variant is present in population databases (rs28936396, gnomAD 0.09%). This missense change has been observed in individual(s) with glutathione synthetase deficiency (PMID: 8896573, 11445798). 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: 8529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GSS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GSS function (PMID: 8896573, 10861239). This variant disrupts the p.Arg125 amino acid residue in GSS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15717202, 26669244, 28267090). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 02, 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.373C>T (p.Arg125Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 5.2e-05 in 251436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GSS causing Glutathione Synthetase Deficiency (5.2e-05 vs 0.003), allowing no conclusion about variant significance. c.373C>T has been reported in the literature in individuals affected with Glutathione Synthetase Deficiency (examples: Shi_1996 and Firas Alqarajeh_2020 ). These data indicate that the variant may be associated with disease. Multiple reports have provided experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Shi_1996 and Njalsson_2000). In addition, another missense variant in the same residue (p.Arg125His) is associated with Glutathione synthetase deficiency (PMID 28267090). The following publications have been ascertained in the context of this evaluation (PMID: 8896573, 10861239). ClinVar contains an entry for this variant (Variation ID: 8529). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Glutathione synthetase deficiency with 5-oxoprolinuria;C1856399:Glutathione synthetase deficiency without 5-oxoprolinuria

Pathogenic:1

Feb 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

May 04, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

.;D;.;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;H;H;.

PhyloP100

9.9

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.8

D;.;.;.;.

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;.;.;.;.

Polyphen

1.0

D;.;D;D;.

Vest4

0.99

MVP

0.99

MPC

0.85

ClinPred

0.99

GERP RS

5.8

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.96

gMVP

0.93

Mutation Taster

=130/170

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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