Submissions for variant NM_002860.4(ALDH18A1):c.809-3T>G

gnomAD frequency: 0.00001  dbSNP: rs755947818

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001104412	SCV001261278	uncertain significance	ALDH18A1-related de Barsy syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769089	SCV002309982	uncertain significance	Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome	2024-06-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the ALDH18A1 gene. It does not directly change the encoded amino acid sequence of the ALDH18A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs755947818, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ALDH18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 878097). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV002280160	SCV002568457	uncertain significance	not provided	2022-02-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing
PreventionGenetics, part of Exact Sciences	RCV004528386	SCV004106389	uncertain significance	ALDH18A1-related disorder	2023-05-25	criteria provided, single submitter	clinical testing	The ALDH18A1 c.809-3T>G variant is predicted to interfere with splicing. This variant is predicted to weaken the nearby canonical splice site (Alamut Visual Plus v.1.6.1). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-97388252-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV002280160	SCV005435107	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	ALDH18A1: PM2, PP3