rs386833549

Variant names:

• chr9-6554703-C-G
• rs386833549
• NM_000170.3:c.2281G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-6554703-C-G
• chr9-6554703-C-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5

The NM_000170.3(GLDC):​c.2281G>C​(p.Gly761Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G761G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.54
• Publications: 6 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 17 ACMG points.

• PS1: Transcript NM_000170.3 (GLDC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000170.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 9-6554703-C-G is Pathogenic according to our data. Variant chr9-6554703-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11986.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.2281G>C	p.Gly761Arg	missense_variant	Exon 19 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.2281G>C	p.Gly761Arg	missense_variant	Exon 19 of 25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Glycine encephalopathy Pathogenic:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Glycine encephalopathy 1 Pathogenic:1

Sep 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.5	H;.;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.6	D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.91		Loss of relative solvent accessibility (P = 0.0071);.;.;
MVP		1.0
MPC		0.34
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.00090	Neutral
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs386833549; hg19: chr9-6554703;