ClinVar Miner

Submissions for variant NM_002860.4(ALDH18A1):c.1994G>A (p.Arg665Gln)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV004590967 SCV005080538 uncertain significance not provided 2024-04-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32798076, 35464835, 29915212)
Labcorp Genetics (formerly Invitae), Labcorp RCV005220960 SCV005861878 likely pathogenic Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome 2025-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 665 of the ALDH18A1 protein (p.Arg665Gln). This variant is present in population databases (rs766264810, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 29915212, 35464835). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3252995). Invitae Evidence 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 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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