NM_000170.3:c.2962C>T

Variant names:

• chr9-6533118-G-A
• rs1288008254
• NM_000170.3:c.2962C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000170.3(GLDC):​c.2962C>T​(p.Arg988Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,056 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R988Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 2.35
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000170.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-6533117-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 554292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 9-6533118-G-A is Pathogenic according to our data. Variant chr9-6533118-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 554524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.2962C>T	p.Arg988Trp	missense	Exon 25 of 25	NP_000161.2	P23378

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.2962C>T	p.Arg988Trp	missense	Exon 25 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000638233.1	TSL:1	n.1397C>T		non_coding_transcript_exon	Exon 11 of 11
	GLDC	ENST00000639443.1	TSL:1	n.2530C>T		non_coding_transcript_exon	Exon 21 of 21

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460056 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726532

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110356

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000930 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Glycine encephalopathy 1 (4)
1	-	-	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.86		Gain of glycosylation at T985 (P = 0.0502)
MVP		0.98
MPC		0.32
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.85
gMVP		0.98
Mutation Taster		=11/89	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: rs1288008254; hg19: chr9-6533118;