14-50247165-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024884.3(L2HGDH):c.1285G>A(p.Gly429Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 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 Uncertain significance (★).
Frequency
Consequence
NM_024884.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
L2HGDH | ENST00000267436.9 | c.1285G>A | p.Gly429Arg | missense_variant | Exon 10 of 10 | 1 | NM_024884.3 | ENSP00000267436.4 | ||
L2HGDH | ENST00000261699.8 | c.1197-9440G>A | intron_variant | Intron 9 of 9 | 1 | ENSP00000261699.4 | ||||
L2HGDH | ENST00000421284.7 | c.1285G>A | p.Gly429Arg | missense_variant | Exon 10 of 11 | 2 | ENSP00000405559.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251284Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135814
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727234
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
L-2-hydroxyglutaric aciduria Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 429 of the L2HGDH protein (p.Gly429Arg). This variant is present in population databases (rs751508205, gnomAD 0.003%). 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. 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 not expected to disrupt L2HGDH protein function. ClinVar contains an entry for this variant (Variation ID: 1436029). This variant has not been reported in the literature in individuals affected with L2HGDH-related conditions. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at