NM_000170.3:c.24G>A

Variant names:

• chr9-6645476-C-T
• rs1163356968
• NM_000170.3:c.24G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000170.3(GLDC):​c.24G>A​(p.Trp8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,117,104 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GLDC NM_000170.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.28
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
• glycine encephalopathy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

LINC02851 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 399 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-6645476-C-T is Pathogenic according to our data. Variant chr9-6645476-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 553731.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.24G>A	p.Trp8*	stop_gained	Exon 1 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.24G>A	p.Trp8*	stop_gained	Exon 1 of 25	1	NM_000170.3	ENSP00000370737.4
LINC02851	ENST00000813373.1	n.124+550C>T		intron_variant	Intron 1 of 2
LINC02851	ENST00000813380.1	n.405+550C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000107 AC: 12 AN: 1117104 Hom.: 0 Cov.: 30 AF XY: 0.00000557 AC XY: 3 AN XY: 538808

African (AFR) AF: 0.0000443 AC: 1 AN: 22558

American (AMR) AF: 0.00 AC: 0 AN: 11500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14624

East Asian (EAS) AF: 0.00 AC: 0 AN: 23926

South Asian (SAS) AF: 0.00 AC: 0 AN: 31138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2944

European-Non Finnish (NFE) AF: 0.0000106 AC: 10 AN: 942116

Other (OTH) AF: 0.0000226 AC: 1 AN: 44214

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine encephalopathy Pathogenic:1

Oct 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 553731). This premature translational stop signal has been observed in individual(s) with glycine encephalopathy (PMID: 27362913). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp8*) 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). For these reasons, this variant has been classified as Pathogenic. -

GLDC-related disorder Pathogenic:1

Dec 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GLDC c.24G>A variant is predicted to result in premature protein termination (p.Trp8*). This variant was reported with a second GLDC variant in two individuals with non-ketotic hyperglycinemia (Coughlin et al. 2017. PubMed ID: 27362913). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in GLDC are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Glycine encephalopathy 1 Pathogenic:1

Sep 05, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.52	D
PhyloP100		1.3
Vest4		0.52
GERP RS		2.6
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=1/199	disease causing (ClinVar)

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

dbSNP: rs1163356968; hg19: chr9-6645476;