ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.798+1del

dbSNP: rs757359379
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411163 SCV000486715 pathogenic Sjögren-Larsson syndrome 2016-07-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411163 SCV000918410 pathogenic Sjögren-Larsson syndrome 2018-08-23 criteria provided, single submitter clinical testing Variant summary: ALDH3A2 c.798+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site, while another predicts the weakening of a 5' donor site. These predictions are supported by RT-PCR assays that revealed aberrant splicing in a homozygous patient's fibroblasts and FALDH enzyme activity assays showing activity levels of <10% of controls (Rizzo_1999, Rizzo_2010). The variant allele was found at a frequency of 8.9e-06 in 112548 control chromosomes (ExAC). The variant, c.798+1delG, has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (Rizzo_1999, Rizzo_2010). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001231409 SCV001403929 pathogenic not provided 2023-09-20 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 5 of the ALDH3A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). This variant is present in population databases (rs757359379, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Sjögren-Larsson syndrome (PMID: 10577908, 30157790). ClinVar contains an entry for this variant (Variation ID: 371195). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 10577908). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000411163 SCV001459272 pathogenic Sjögren-Larsson syndrome 2020-09-16 no assertion criteria provided clinical testing

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