rs937345512
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024884.3(L2HGDH):c.208C>T(p.Arg70*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,606 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024884.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152102Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251366Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135860
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461504Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 727090
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152102Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16134148, 25525159, 31589614, 31130284) -
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PP4, PM2_moderate, PM3, PS4, PVS1 -
L-2-hydroxyglutaric aciduria Pathogenic:2
ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated -
This sequence change creates a premature translational stop signal (p.Arg70*) in the L2HGDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in L2HGDH are known to be pathogenic (PMID: 16134148, 20052767). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with L-2-hydroxyglutaric aciduria (PMID: 16134148). ClinVar contains an entry for this variant (Variation ID: 580563). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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