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

dbSNP: rs1036733598

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410648	SCV000485804	likely pathogenic	Sjögren-Larsson syndrome	2016-02-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861368	SCV002127026	pathogenic	not provided	2024-01-11	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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Sjögren-Larsson syndrome (PMID: 15241804, 16536828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 370471). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410648	SCV003800745	likely pathogenic	Sjögren-Larsson syndrome	2023-01-10	criteria provided, single submitter	clinical testing	Variant summary: ALDH3A2 c.1108-1G>T 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. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251256 control chromosomes. To our knowledge, no occurrence of c.1108-1G>T in individuals affected with Sjogren-Larsson Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Another splice site variant at the same position has been classified by our lab as pathogenic (c.1108-1G>C). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.