20-34928887-G-A

Variant names:

• chr20-34928887-G-A
• NM_000178.4:c.1366C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000178.4(GSS):​c.1366C>T​(p.His456Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GSS NM_000178.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4	c.1366C>T	p.His456Tyr	missense_variant	Exon 13 of 13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.1366C>T	p.His456Tyr	missense_variant	Exon 13 of 13		NP_001309423.1
GSS	NM_001322495.1	c.1366C>T	p.His456Tyr	missense_variant	Exon 13 of 13		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1	c.1366C>T	p.His456Tyr	missense_variant	Exon 13 of 13		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1366C>T (p.H456Y) alteration is located in exon 13 (coding exon 12) of the GSS gene. This alteration results from a C to T substitution at nucleotide position 1366, causing the histidine (H) at amino acid position 456 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;D;D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;.;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.6	.;M;M;M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	.;N;.;.;N
REVEL	Uncertain	0.61
Sift	Benign	0.29	.;T;.;.;T
Sift4G	Benign	0.78	.;T;.;.;T
Polyphen		1.0	.;D;D;D;.
Vest4		0.32, 0.49
MutPred		0.52		.;Loss of disorder (P = 0.0509);Loss of disorder (P = 0.0509);Loss of disorder (P = 0.0509);.;
MVP		0.94
MPC		0.76
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.63
gMVP		0.77
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

hg19: chr20-33516690;