ClinVar Miner

Submissions for variant NM_002860.4(ALDH18A1):c.809-1G>C

dbSNP: rs1202802893
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town RCV003320377 SCV003930389 uncertain significance Hereditary spastic paraplegia 9A 2024-05-22 criteria provided, single submitter research PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00006491 (0.007%; 1/15406 alleles in European non-Finnish population) and in gnomAD v3.1.2 is 0.00001470 (0.001%; 1/68028 alleles in European non-Finnish population) and the variant is absent from an internal database of 1074 control alleles. This variant has a MAF of 0.032% (32/100000 alleles) in an internal database from the Netherlands. PS4 not met: variant identified in 3 probands by clinical testing (SCV001929264.1, SCV001952732.1, SCV001970262.1) and classified as likely pathogenic for AR HSP (variant was confirmed in trans with another ALDH18A1 VUS and the parents were unaffected heterozygous carriers). PVS1 met: null variant (canonical +/- 1 or 2 splice site variant, predicted to cause exon skipping or use of a cryptic splice site which disrupts reading frame and is predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF (via a dominant negative effect) is a reported mechanism of disease (PMID: 26297558). PP3 not evaluated as PVS1 applied. Sequencing funded by the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium: https://create.rarediseasesnetwork.org.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001703400 SCV001929264 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001703400 SCV001952732 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001703400 SCV001970262 pathogenic not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004536264 SCV004761385 likely pathogenic ALDH18A1-related disorder 2023-10-21 no assertion criteria provided clinical testing The ALDH18A1 c.809-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the heterozygous state in an individual with hereditary spastic paraplegia; however, a second ALDH18A1 variant was not detected in this individual (Mahungu et al. 2023. PubMed ID: 37712079). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-97388250-C-G). Variants that disrupt the consensus splice acceptor site in ALDH18A1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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