rs121909308

Positions:

• chr20-34935611-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000178.4(GSS):​c.799C>T​(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: GSS NM_000178.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.13

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 20-34935611-G-A is Pathogenic according to our data. Variant chr20-34935611-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSS	NM_000178.4	c.799C>T	p.Arg267Trp	missense_variant	9/13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.799C>T	p.Arg267Trp	missense_variant	9/13		NP_001309423.1
GSS	NM_001322495.1	c.799C>T	p.Arg267Trp	missense_variant	9/13		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1	c.799C>T	p.Arg267Trp	missense_variant	9/13		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251450 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461128 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 726922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutathione synthetase deficiency with 5-oxoprolinuria Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2024	Variant summary: GSS c.799C>T (p.Arg267Trp) results in a non-conservative amino acid change located in the glutathione synthase, substrate-binding domain (IPR004887) of 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 1.2e-05 in 251450 control chromosomes. c.799C>T has been reported in the literature in the compound heterozygous state in individuals affected with Glutathione Synthetase Deficiency (e.g. Shi_1996, Dahl_1997). These data indicate that the variant may be associated with disease. In vitro studies in e.coli report that this variant results in absent GSS activity (e.g. Shi_1996) and kinetic impairment of enzyme function (e.g.Njalsson_2000). The following publications have been ascertained in the context of this evaluation (PMID: 9215686, 10861239, 8896573). ClinVar contains an entry for this variant (Variation ID: 8527). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -

Inherited glutathione synthetase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

Experimental studies have shown that this missense change affects GSS function (PMID: 8896573, 10861239, 30581542). 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. ClinVar contains an entry for this variant (Variation ID: 8527). This missense change has been observed in individual(s) with glutathione synthetase deficiency (PMID: 8896573, 11445798). This variant is present in population databases (rs121909308, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 267 of the GSS protein (p.Arg267Trp). This variant disrupts the p.Arg267 amino acid residue in GSS. Other variant(s) that disrupt this residue have been observed in individuals with GSS-related conditions (PMID: 31198081), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;.;D;.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.;H;H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.5	.;D;.;.;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	.;D;.;.;.;D
Sift4G	Pathogenic	0.0	.;D;.;.;.;D
Polyphen		1.0	.;D;.;D;D;.
Vest4		0.94, 0.96
MutPred		0.97		.;Loss of catalytic residue at R267 (P = 0.0741);Loss of catalytic residue at R267 (P = 0.0741);Loss of catalytic residue at R267 (P = 0.0741);Loss of catalytic residue at R267 (P = 0.0741);.;
MVP		0.99
MPC		0.82
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121909308; hg19: chr20-33523414; COSMIC: COSV53814739; COSMIC: COSV53814739;