rs1554646529

Positions:

• 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	Protein	UniProt
GLDC	NM_000170.3	c.1723G>T	p.Glu575Ter	stop_gained	15/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.1723G>T	p.Glu575Ter	stop_gained	15/25	1	NM_000170.3	ENSP00000370737	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	Labcorp Genetics (formerly Invitae), Labcorp	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;