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NM_000170.3(GLDC):c.2197G>T (p.Ala733Ser) AND Non-ketotic hyperglycinemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 17, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002714950.3

Allele description [Variation Report for NM_000170.3(GLDC):c.2197G>T (p.Ala733Ser)]

NM_000170.3(GLDC):c.2197G>T (p.Ala733Ser)

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.2197G>T (p.Ala733Ser)
HGVS:
  • NC_000009.12:g.6556158C>A
  • NG_016397.1:g.94535G>T
  • NM_000170.3:c.2197G>TMANE SELECT
  • NP_000161.2:p.Ala733Ser
  • NP_000161.2:p.Ala733Ser
  • LRG_643t1:c.2197G>T
  • LRG_643:g.94535G>T
  • LRG_643p1:p.Ala733Ser
  • NC_000009.11:g.6556158C>A
  • NM_000170.2:c.2197G>T
Protein change:
A733S
Molecular consequence:
  • NM_000170.3:c.2197G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002990447Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Mar 17, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

Coughlin CR 2nd, Swanson MA, Kronquist K, Acquaviva C, Hutchin T, Rodríguez-Pombo P, Väisänen ML, Spector E, Creadon-Swindell G, Brás-Goldberg AM, Rahikkala E, Moilanen JS, Mahieu V, Matthijs G, Bravo-Alonso I, Pérez-Cerdá C, Ugarte M, Vianey-Saban C, Scharer GH, Van Hove JL.

Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Epub 2016 Jun 30. Erratum in: Genet Med. 2018 Sep;20(9):1098. doi: 10.1038/gim.2017.232.

PubMed [citation]
PMID:
27362913

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002990447.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala733 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27362913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with GLDC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 733 of the GLDC protein (p.Ala733Ser).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024