chr9-6565391-C-G

Variant names:

• chr9-6565391-C-G
• rs763517274
• NM_000170.3:c.1889G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000170.3(GLDC):​c.1889G>C​(p.Arg630Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,652 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.21
• 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

ENSG00000296224 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 9-6565391-C-G is Pathogenic according to our data. Variant chr9-6565391-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 462860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.1889G>C	p.Arg630Pro	missense_variant	Exon 16 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.1889G>C	p.Arg630Pro	missense_variant	Exon 16 of 25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461652 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Pathogenic:2

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLDC protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLDC function (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 462860). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 26179960; Invitae). In at least one individual the data is consistent with 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 replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 630 of the GLDC protein (p.Arg630Pro). -

Jun 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLDC c.1889G>C (p.Arg630Pro) results in a non-conservative amino acid change located in the Aromatic amino acid beta-eliminating lyase/threonine aldolase domain (IPR001597) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.1889G>C has been reported in the literature in the compound heterozygous state in at least 1 individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Coughlin_2017, Swanson_2015, Swanson_2022). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in ~10% of normal activity and reduced protein stability as determined by Western blotting (example, Swanson_2015). The following publications have been ascertained in the context of this evaluation (PMID: 27362913, 26179960, 35357708). ClinVar contains an entry for this variant (Variation ID: 462860). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Glycine encephalopathy 1 Pathogenic:1

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;.;.
PhyloP100		4.2
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		0.89	P;.;.;.
Vest4		0.68
MutPred		0.68		Loss of catalytic residue at R630 (P = 0.0099);.;.;.;
MVP		1.0
MPC		0.23
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.011	Neutral
Varity_R		0.89
gMVP		0.94
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs763517274; hg19: chr9-6565391;