rs386833574

Variant names:

• chr9-6645471-AG-A
• rs386833574
• NM_000170.3:c.28delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000170.3(GLDC):​c.28delC​(p.Leu10CysfsTer81) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLDC NM_000170.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.660
• Publications: 4 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

LINC02851 (HGNC:):

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 397 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-6645471-AG-A is Pathogenic according to our data. Variant chr9-6645471-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 56092.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.28delC	p.Leu10CysfsTer81	frameshift_variant	Exon 1 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.28delC	p.Leu10CysfsTer81	frameshift_variant	Exon 1 of 25	1	NM_000170.3	ENSP00000370737.4
LINC02851	ENST00000813373.1	n.124+546delG		intron_variant	Intron 1 of 2
LINC02851	ENST00000813380.1	n.405+546delG		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine encephalopathy Pathogenic:2

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with glycine encephalopathy (PMID: 16601880). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu10Cysfs*81) in the GLDC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). -

Glycine encephalopathy 1 Pathogenic:1

Nov 30, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386833574; hg19: chr9-6645471;