rs28936396

Positions:

chr20-34942606-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely 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:4

Conservation

PhyloP100: 9.91

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity GSHB_HUMAN

PM2

Very rare variant in population databases, with high coverage;

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 [Likely_pathogenic]. Clinvar id is 8529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-34942606-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GSS	NM_000178.4 linkuse as main transcript	c.373C>T	p.Arg125Cys	missense_variant	5/13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1 linkuse as main transcript	c.373C>T	p.Arg125Cys	missense_variant	5/13		NP_001309423.1
GSS	NM_001322495.1 linkuse as main transcript	c.373C>T	p.Arg125Cys	missense_variant	5/13		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1 linkuse as main transcript	c.373C>T	p.Arg125Cys	missense_variant	5/13		NM_000178.4	ENSP00000498303	P1	P48637-1

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

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251436

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135900

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000243

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.000845

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000167

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inherited glutathione synthetase deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 28, 2022	Variant summary: GSS c.373C>T (p.Arg125Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251436 control chromosomes (gnomAD). This frequency is not higher than predicted 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). Other variant(s) that disrupt this residue have been reported to be associated with Glutathione synthetase deficiency (PMID 28267090). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 04, 2023

- -

Glutathione synthetase deficiency with 5-oxoprolinuria

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1996

- -

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

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;.

MutationTaster

Benign

1.0

A;A;A

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

Varity_R

0.96

gMVP

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over