rs149133229

Positions:

• chr9-6604646-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000170.3(GLDC):​c.1000T>C​(p.Phe334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,613,774 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 8.69

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.1000T>C	p.Phe334Leu	missense_variant	7/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.1000T>C	p.Phe334Leu	missense_variant	7/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000318 AC: 80 AN: 251400 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135874

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000798 AC: 1167 AN: 1461580 Hom.: 2 Cov.: 32 AF XY: 0.000821 AC XY: 597 AN XY: 727106

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74370

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000459 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 07, 2023	The GLDC c.1000T>C variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE (PS4_Supporting, PM3, PP3) The GLDC c.1000T>C variant is a single nucleotide change in exon 7/25 of the GLDC gene, which is predicted to change the amino acid phenylalanine at position 334 in the protein to leucine. This variant has been previously reported in a patient with Glycine encephalopathy in trans with a deletion of the GLDC gene (PMID:32421718) (PS4_Supporting) (PM3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs149133229) and in the HGMD database: CM1510140. It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 367196). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 334 of the GLDC protein (p.Phe334Leu). This variant is present in population databases (rs149133229, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of glycine encephalopathy and/or nonketotic hyperglycinemia (PMID: 26179960, 32421718). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 367196). 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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	Reported previously in an individual with severe nonketotic hyperglycinemia who harbored a deletion of exons 1-25 in the GLDC gene on the opposite allele (Swanson et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32421718, 26179960, 27362913) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 19, 2024

Variant summary: GLDC c.1000T>C (p.Phe334Leu) results in a non-conservative amino acid change located in the Glycine cleavage system P-protein, N-terminal domain (IPR049315) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.00032 vs 0.0031), allowing no conclusion about variant significance. c.1000T>C has been reported in the literature as a compound heterozygous genotype with deletion of exons 1-25 in at-least one individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Swanson_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27362913, 32421718, 26179960). ClinVar contains an entry for this variant (Variation ID: 367196). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.1000T>C (p.F334L) alteration is located in exon 7 (coding exon 7) of the GLDC gene. This alteration results from a T to C substitution at nucleotide position 1000, causing the phenylalanine (F) at amino acid position 334 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD), the GLDC c.1000T>C alteration was not observed, with coverage at this position. This amino acid position is highly conserved in available vertebrate species. The p.F334L alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 05, 2021

ACMG classification criteria: PM2, PM3, PP3 -

Glycine encephalopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	0.083
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Pathogenic	0.83
Sift	Benign	0.30	T;.
Sift4G	Benign	0.25	T;.
Polyphen		0.062	B;.
Vest4		0.97
MutPred		0.74		Gain of MoRF binding (P = 0.1142);.;
MVP		0.98
MPC		0.34
ClinPred		0.12	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149133229; hg19: chr9-6604646;