rs1554646529

chr9-6587268-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000170.3(GLDC):c.1723G>T(p.Glu575Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000132 in 152,056 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: GLDC NM_000170.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.85

Genes affected

GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-6587268-C-A is Pathogenic according to our data. Variant chr9-6587268-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6587268-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.1723G>T	p.Glu575Ter	stop_gained	15/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.1723G>T	p.Glu575Ter	stop_gained	15/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553781). This premature translational stop signal has been observed in individual(s) with clinical features of nonketotic hyperglycinemia (PMID: 27362913). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu575*) in the GLDC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2018

The E575X variant in the GLDC gene has been reported previously, in the compound heterozygous state along with a missense variant, in an individual with a suspected diagnosis of nonketotic hyperglycinemia (Coughlin et al., 2017). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E575X variant is not observed in large population cohorts (Lek et al., 2016). We interpret E575X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.82
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1554646529; hg19: chr9-6587268; COSMIC: COSV58685784; COSMIC: COSV58685784;