rs191905539

Positions:

chr9-6610328-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000170.3(GLDC):c.499G>T(p.Glu167Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,022 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E167E) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GLDC
NM_000170.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.57

Variant links:

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]

GLDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 9-6610328-C-A is Pathogenic according to our data. Variant chr9-6610328-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6610328-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3 linkuse as main transcript	c.499G>T	p.Glu167Ter	stop_gained	4/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8 linkuse as main transcript	c.499G>T	p.Glu167Ter	stop_gained	4/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.000955

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251296

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000138

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00124

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:

0.000945

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Non-ketotic hyperglycinemia

Pathogenic:6

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 29, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 31, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Glu167*) 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). This variant is present in population databases (rs191905539, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with glycine encephalopathy, also known as non-ketotic hyperglycinemia (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 370365). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2020	Variant summary: GLDC c.499G>T (p.Glu167X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251296 control chromosomes. c.499G>T has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) in the homozygous and compound heterozygous states (Swanson_2015, Coughlin_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 01, 2024	The p.Glu167X variant in GLDC has been reported in the compound heterozygous state or homozygous state in at least 3 individuals with glycine encephalopathy (Swanson 2015 PMID: 26179960, Coughlin 2017 PMID: 27362913). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 370365) and has been identified in 0.12% (19/15276) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 167, which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the GLDC gene is an established disease mechanism in autosomal recessive glycine encephalopathy, also known as nonketotic hyperglycinemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive glycine encephalopathy. ACMG/AMP Criteria applied: PVS1, PM3. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.499G>T (p.E167*) alteration, located in exon 4 (coding exon 4) of the GLDC gene, consists of a G to T substitution at nucleotide position 499. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 167. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/251296) total alleles studied. The highest observed frequency was 0.016% (1/6132) of Other alleles. This mutation has been detected in the homozygous and compound heterozygous states in individuals with nonketotic hyperglycemia (Swanson, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26179960) -

GLDC-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2024

The GLDC c.499G>T variant is predicted to result in premature protein termination (p.Glu167*). This variant was reported as a recurrent variant for nonketotic hyperglycinemia (see, for example, Swanson et al. 2015. PubMed ID: 26179960). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in GLDC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

Vest4

0.85

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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