NM_000170.3:c.2962C>T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000170.3(GLDC):c.2962C>T(p.Arg988Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R988Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000170.3 missense
Scores
Clinical Significance
Conservation
Publications
- glycine encephalopathyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
- glycine encephalopathy 1Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
- infantile glycine encephalopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- neonatal glycine encephalopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- atypical glycine encephalopathyInheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460056Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726532 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Glycine encephalopathy 1 Pathogenic:2Uncertain:1
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This submission and the accompanying classification are no longer maintained by the submitter.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. -
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Glycine encephalopathy Pathogenic:1
This sequence change replaces arginine with tryptophan at codon 988 of the GLDC protein (p.Arg988Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with glycine encephalopathy (PMID: 27362913). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554524). 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. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at