rs772574530

chr9-6533142-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000170.3(GLDC):c.2938A>G(p.Asn980Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N980N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 4.95

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-6533142-T-C is Pathogenic according to our data. Variant chr9-6533142-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402186.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr9-6533142-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.15486988).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.2938A>G	p.Asn980Asp	missense_variant	25/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.2938A>G	p.Asn980Asp	missense_variant	25/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251428 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461488 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000983

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 15, 2022	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 980 of the GLDC protein (p.Asn980Asp). This variant is present in population databases (rs772574530, gnomAD 0.02%). This missense change has been observed in individual(s) with GLDC-related condition (PMID: 26539891). ClinVar contains an entry for this variant (Variation ID: 402186). 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 not expected to disrupt GLDC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 05, 2022

Variant summary: GLDC c.2938A>G (p.Asn980Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251428 control chromosomes. c.2938A>G has been reported in the literature in one individual affected with intellectual disability and seizures. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.90	L;.;.;.
MutationTaster	Benign	0.51	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N;.;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.26	T;.;.;.
Sift4G	Benign	0.43	T;.;.;.
Polyphen		0.14	B;.;.;.
Vest4		0.20
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0249);.;.;.;
MVP		0.81
MPC		0.050
ClinPred		0.21	T
GERP RS		5.1
Varity_R		0.42
gMVP		0.67

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: rs772574530; hg19: chr9-6533142;