rs1554646653

chr9-6588641-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000170.3(GLDC):c.1642C>G(p.Leu548Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L548P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.84

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 10 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, 5 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• PP5: Variant 9-6588641-G-C is Pathogenic according to our data. Variant chr9-6588641-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551376.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-6588641-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.1642C>G	p.Leu548Val	missense_variant	13/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.1642C>G	p.Leu548Val	missense_variant	13/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Polyphen		0.22	B
Vest4		0.94
MutPred		0.60		Gain of catalytic residue at L548 (P = 0.0718);
MVP		0.98
MPC		0.053
ClinPred		0.90	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.82

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: rs1554646653; hg19: chr9-6588641;