rs752560204

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_000178.4(GSS):c.4delG(p.Ala2ProfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

GSS
NM_000178.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.89

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 Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-34951848-GC-G is Pathogenic according to our data. Variant chr20-34951848-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338302.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4 link	c.4delG	p.Ala2ProfsTer14	frameshift_variant	Exon 2 of 13	ENST00000651619.1	NP_000169.1	P48637-1V9HWJ1
GSS	NM_001322494.1 link	c.4delG	p.Ala2ProfsTer14	frameshift_variant	Exon 2 of 13		NP_001309423.1	P48637-1V9HWJ1
GSS	NM_001322495.1 link	c.4delG	p.Ala2ProfsTer14	frameshift_variant	Exon 2 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.4delG	p.Ala2ProfsTer14	frameshift_variant	Exon 2 of 13		NM_000178.4	ENSP00000498303.1		P48637-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251230

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00463

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000164

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.000125

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutathione synthetase deficiency with 5-oxoprolinuria

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 14, 2024	This sequence change creates a premature translational stop signal (p.Ala2Profs*14) in the GSS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GSS are known to be pathogenic (PMID: 12638941, 15717202). This variant is present in population databases (rs752560204, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with gluthathione synthetase deficiency (PMID: 8896573). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 338302). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -

Inherited glutathione synthetase deficiency

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2016	Variant summary: The c.4delG (p.Ala2Profs) variant in GSS gene is a nonsense change that results in the loss of the 460 amino acids of GSS (~98%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The results of functional showed less than 10% GSS activity in pts fibroblasts as well as in bacterial expression system. . The variant is present in the large control population dataset of ExAC at a low frequency 0.0002 (25/120304 chrs tested), exclusively in individuals of European descent (0.00038; 15/66140).The latter frequency does not exceed the maximal expected frequency of a pathogenic allele (0.003) in this gene. The variant of interest has been reported in two brothers presented with oxoprolinuria, metabolic acidosis, haemolytic anemia and mental retardation. Taking together, the variant was classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The GSS c.4delG (p.Ala2ProfsTer14) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ala2ProfsTer14 variant has been reported in one study in which it was found in a compound heterozygous state with a missense variant in two siblings with glutathione synthetase (GS) deficiency. Control data are unavailable for this variant which is reported at a frequency of 0.0004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E. coli and yeast demonstrate that the variants result in 2% of expression levels and 10% GSS activity as compared to wildtype (Shi et al. 1996). Due to the potential impact of frameshift variants and supporting evidence, the p.Ala2ProfsTer14 variant is classified as a variant of unknown significance but suspicious for pathogenicity for glutathione synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 10, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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