Submissions for variant NM_000382.3(ALDH3A2):c.1108-1G>C

dbSNP: rs1036733598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411369	SCV000485779	pathogenic	Sjögren-Larsson syndrome	2016-02-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411369	SCV001431939	pathogenic	Sjögren-Larsson syndrome	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: ALDH3A2 c.1108-1G>C 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: four predict the variant abolishes a 3' acceptor site. A publication also reported experimental evidence confirming that this variant affects mRNA splicing, resulting in exon skipping (Rizzo_1999). The variant allele was found at a frequency of 4e-06 in 251256 control chromosomes. c.1108-1G>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Sjogren-Larsson Syndrome (Rizzo_1999, Carney_2004, Auada_2006). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated <10% of normal activity in fibroblasts derived from homozygous patients (Carney_2004, Auada_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861367	SCV002235102	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 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 (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with Sjogren-Larsson syndrome (PMID: 10577908, 15241804). ClinVar contains an entry for this variant (Variation ID: 370452). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001861367	SCV003837173	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Canonical splice site variant shown to result in a null allele by splicing studies in a gene for which loss-of-function is a known mechanism of disease (Rizzo et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29742247, 16927642, 10577908, 34426522, 29899769, 15241804, 31589614, 25525159, 16536828)
Fulgent Genetics, Fulgent Genetics	RCV000411369	SCV005644804	pathogenic	Sjögren-Larsson syndrome	2024-04-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000411369	SCV002093186	pathogenic	Sjögren-Larsson syndrome	2020-12-15	no assertion criteria provided	clinical testing