rs587783517
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_152783.5(D2HGDH):c.566C>T(p.Pro189Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,858 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P189P) has been classified as Likely benign.
Frequency
Consequence
NM_152783.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
D2HGDH | NM_152783.5 | c.566C>T | p.Pro189Leu | missense_variant | 5/10 | ENST00000321264.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
D2HGDH | ENST00000321264.9 | c.566C>T | p.Pro189Leu | missense_variant | 5/10 | 1 | NM_152783.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249644Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135190
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461686Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727124
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
D-2-hydroxyglutaric aciduria 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. Experimental studies have shown that this missense change affects D2HGDH function (PMID: 30908763, 33431826). ClinVar contains an entry for this variant (Variation ID: 158422). This missense change has been observed in individual(s) with D-2-hydroxyglutaric aciduria (PMID: 20020533). This variant is present in population databases (rs587783517, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 189 of the D2HGDH protein (p.Pro189Leu). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 19, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at