9-6604646-A-G

Position:

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 8.69

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.1000T>C	p.Phe334Leu	missense_variant	7/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

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:

AN:

251400

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135874

show subpopulations

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.:

Cov.:

AF XY:

0.000821

AC XY:

597

AN XY:

727106

show subpopulations

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:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74370

show subpopulations

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.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;.

Eigen

Benign

0.083

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over