rs864321670
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_002860.4(ALDH18A1):c.755G>A(p.Arg252Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252G) has been classified as Uncertain significance.
Frequency
Consequence
NM_002860.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH18A1 | NM_002860.4 | c.755G>A | p.Arg252Gln | missense_variant | 7/18 | ENST00000371224.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH18A1 | ENST00000371224.7 | c.755G>A | p.Arg252Gln | missense_variant | 7/18 | 1 | NM_002860.4 | P3 | |
ALDH18A1 | ENST00000371221.3 | c.749G>A | p.Arg250Gln | missense_variant | 7/18 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2021 | Published functional studies suggest a damaging effect; specifically, in vitro functional expression assays show the mutant protein localizes normally to the mitochondria but low enzymatic activity (Panza et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33573605, 26026163, 26297558, 31692161) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Hereditary spastic paraplegia 9A Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Feb 08, 2018 | - - |
ALDH18A1 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 17, 2020 | The ALDH18A1 c.755G>A (p.Arg252Gln) variant is a missense variant and has been reported in a heterozygous state in at least three unrelated affected individuals presenting with moderate to severe pyramidal signs, pes cavus, cataracts, gastro-oesophageal reflux, chronic cellulitis, and cortical atrophy (Panza et al. 2006; Coutelier et al. 2015). Segregation of the p.Arg252Gln variant with disease was observed in one family in seven affected members over three generations and was absent in all unaffected members (Panza et al. 2016). Functional studies with recombinant p.Arg252Gln variant protein demonstrated that the enzyme activity was reduced compared to wild type (Panza et al. 2016). In addition, the p.Arg252 residue lies in the glutamate-5-kinase domain and is predicted by modelling to lie within the active site (Panza et al. 2006; Coutelier et al. 2015). The p.Arg252Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of ACMG criteria, the p.Arg252Gln variant is classified as pathogenic for ALDH18A1 deficiency. - |
de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 252 of the ALDH18A1 protein (p.Arg252Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 26026163, 26297558). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217117). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH18A1 protein function. Experimental studies have shown that this missense change affects ALDH18A1 function (PMID: 26297558). 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