14-50247128-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_024884.3(L2HGDH):c.1322C>T(p.Pro441Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P441R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_024884.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
L2HGDH | NM_024884.3 | c.1322C>T | p.Pro441Leu | missense_variant | 10/10 | ENST00000267436.9 | NP_079160.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
L2HGDH | ENST00000267436.9 | c.1322C>T | p.Pro441Leu | missense_variant | 10/10 | 1 | NM_024884.3 | ENSP00000267436 | P1 | |
L2HGDH | ENST00000261699.8 | c.1197-9403C>T | intron_variant | 1 | ENSP00000261699 | |||||
L2HGDH | ENST00000421284.7 | c.1322C>T | p.Pro441Leu | missense_variant | 10/11 | 2 | ENSP00000405559 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461786Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727196
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
L-2-hydroxyglutaric aciduria Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.P441L in L2HGDH (NM_024884.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.P441L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P441L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 441 of L2HGDH is conserved in all mammalian species. The nucleotide c.1322 in L2HGDH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.