rs769625871
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_000170.3(GLDC):c.2033_2035del(p.Ala678del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A678A) has been classified as Likely benign.
Frequency
Consequence
NM_000170.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.2033_2035del | p.Ala678del | inframe_deletion | 17/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.2033_2035del | p.Ala678del | inframe_deletion | 17/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251452Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135896
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461880Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 09, 2018 | The p.Ala678del variant in GLDC has been reported in one individual with glycine encephalopathy who carried a deletion of exons 3-21 in trans (Swanson 2015). It has also been identified in 1/111670 of European chromosomes by gnomAD (http:// gnomad.broadinstitute.org). This variant is a deletion of one amino acid at posi tion 678 and is not predicted to alter the protein reading-frame. In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Ala678del variant is likely pathogenic. ACMG/AMP criteria applied: PM 2, PM3, PP4, PM4_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 08, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2023 | Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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. Experimental studies have shown that this variant affects GLDC function (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 558242). This variant has been observed in individual(s) with glycine encephalopathy (PMID: 26179960). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs769625871, gnomAD 0.0009%). This variant, c.2033_2035del, results in the deletion of 1 amino acid(s) of the GLDC protein (p.Ala678del), but otherwise preserves the integrity of the reading frame. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at