rs752560204

chr20-34951848-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000178.4(GSS):c.4del(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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 1.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 38 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=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSS	NM_000178.4	c.4del	p.Ala2ProfsTer14	frameshift_variant	2/13	ENST00000651619.1
GSS	NM_001322494.1	c.4del	p.Ala2ProfsTer14	frameshift_variant	2/13
GSS	NM_001322495.1	c.4del	p.Ala2ProfsTer14	frameshift_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSS	ENST00000651619.1	c.4del	p.Ala2ProfsTer14	frameshift_variant	2/13		NM_000178.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152220 Hom.: 0 Cov.: 33

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: 58 AN: 251230 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135816

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.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 89 AN XY: 727184

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: 25 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74354

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.: 0

Bravo AF: 0.000125

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inherited glutathione synthetase deficiency Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 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. -
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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -
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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs752560204; hg19: chr20-33539651;