NM_000170.3(GLDC):c.1940C>T (p.Pro647Leu) AND Non-ketotic hyperglycinemia

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Oct 13, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000284142.20

Allele description [Variation Report for NM_000170.3(GLDC):c.1940C>T (p.Pro647Leu)]

NM_000170.3(GLDC):c.1940C>T (p.Pro647Leu)

Gene:

GLDC:glycine decarboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p24.1

Genomic location:

Preferred name:

NM_000170.3(GLDC):c.1940C>T (p.Pro647Leu)

HGVS:

NC_000009.12:g.6558671G>A
NG_016397.1:g.92022C>T
NM_000170.3:c.1940C>TMANE SELECT
NP_000161.2:p.Pro647Leu
NP_000161.2:p.Pro647Leu
LRG_643t1:c.1940C>T
LRG_643:g.92022C>T
LRG_643p1:p.Pro647Leu
NC_000009.11:g.6558671G>A
NM_000170.2:c.1940C>T

Protein change:

P647L

Links:

dbSNP: rs201135624

NCBI 1000 Genomes Browser:

rs201135624

Molecular consequence:

NM_000170.3:c.1940C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Non-ketotic hyperglycinemia
Synonyms:: Glycine encephalopathy; Nonketotic hyperglycinemia
Identifiers:: MONDO: MONDO:0011612; MedGen: C0751748; Orphanet: 407; OMIM: PS605899; Human Phenotype Ontology: HP:0008288

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000480504	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000794700	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Oct 24, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000833948	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27799067, 28492532
SCV001251760	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 3, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001457123	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.

Loviglio MN, Beck CR, White JJ, Leleu M, Harel T, Guex N, Niknejad A, Bi W, Chen ES, Crespo I, Yan J, Charng WL, Gu S, Fang P, Coban-Akdemir Z, Shaw CA, Jhangiani SN, Muzny DM, Gibbs RA, Rougemont J, Xenarios I, Lupski JR, et al.

Genome Med. 2016 Nov 1;8(1):105.

PubMed [citation]

PMID:: 27799067
PMCID:: PMC5088687

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000480504.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000794700.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000833948.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 647 of the GLDC protein (p.Pro647Leu). This variant is present in population databases (rs201135624, gnomAD 0.01%). This missense change has been observed in individual(s) with Smith-Magenis like phenotype (PMID: 27799067). ClinVar contains an entry for this variant (Variation ID: 254211). 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. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV001251760.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001457123.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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