14-50247174-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_024884.3(L2HGDH):c.1276G>A(p.Gly426Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 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
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
L2HGDH | ENST00000267436.9 | c.1276G>A | p.Gly426Arg | missense_variant | Exon 10 of 10 | 1 | NM_024884.3 | ENSP00000267436.4 | ||
L2HGDH | ENST00000261699.8 | c.1197-9449G>A | intron_variant | Intron 9 of 9 | 1 | ENSP00000261699.4 | ||||
L2HGDH | ENST00000421284.7 | c.1276G>A | p.Gly426Arg | missense_variant | Exon 10 of 11 | 2 | ENSP00000405559.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251272Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135814
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN 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 426 of the L2HGDH protein (p.Gly426Arg). This variant is present in population databases (rs754872991, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with L2HGDH-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at