ClinVar Miner

Submissions for variant NM_002860.4(ALDH18A1):c.2294G>A (p.Arg765Gln)

gnomAD frequency: 0.00002  dbSNP: rs537043237
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000196978 SCV000255322 likely pathogenic ALDH18A1-related de Barsy syndrome 2012-11-20 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814103 SCV001755193 likely pathogenic Abnormality of the nervous system 2021-07-10 criteria provided, single submitter clinical testing
3billion RCV000196978 SCV002572555 pathogenic ALDH18A1-related de Barsy syndrome 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25077174). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.63). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000216888). The variant is in trans with the other variant (NM_002860.4:c.2246G>A, p.Arg749Gln). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV003765290 SCV004569732 uncertain significance Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome 2023-11-16 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 765 of the ALDH18A1 protein (p.Arg765Gln). This variant is present in population databases (rs537043237, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of cutis laxa (PMID: 25077174, 25326637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216888). 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. 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.

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