NM_000170.3:c.2113G>C

Variant names:

• chr9-6556242-C-G
• rs147275962
• NM_000170.3:c.2113G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000170.3(GLDC):​c.2113G>C​(p.Val705Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V705M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 12 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: Uncertain_significance. The variant received 4 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, 8 uncertain in NM_000170.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.2113G>C	p.Val705Leu	missense_variant	Exon 18 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.2113G>C	p.Val705Leu	missense_variant	Exon 18 of 25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.3	L;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D;.;.
Sift4G	Uncertain	0.026	D;.;.
Polyphen		0.21	B;.;.
Vest4		0.57
MutPred		0.57		Loss of catalytic residue at V705 (P = 0.3137);.;.;
MVP		0.95
MPC		0.050
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.63
gMVP		0.89
Mutation Taster		=53/47	polymorphism

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: rs147275962; hg19: chr9-6556242;