Submissions for variant NM_000382.3(ALDH3A2):c.471+1del

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169590	SCV000221098	likely pathogenic	Sjögren-Larsson syndrome	2015-01-29	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169590	SCV000696650	pathogenic	Sjögren-Larsson syndrome	2016-07-08	criteria provided, single submitter	clinical testing	Variant summary: The ALDH3A2 c.471+1delG variant involves the alteration of a conserved intronic nucleotide located at the invariable GT site at the border of intron 3. One in silico tool predicts a damaging outcome for this variant along with 5/5 splice tools predicting the variant to result in the weakening/elimination of the splice donor site in intron 3. These predictions have been confirmed by studies investigating SLS patients who carried the variant and demonstrated that the variant results in altered mRNA and the absence of the full length protein product. This variant was absent in 121396 control chromosomes, but has been reported in multiple SLS patients in either homozygosity or compound heterozygosity with other splice site or frameshift variants, suggesting pathogenicity. In addition, a clinical diagnostic laboratory classified this variant as Likely Pathogenic via ClinVar (without evidence to independently evaluate). Taken together, this variant is classified as Pathogenic.
Invitae	RCV001034892	SCV001198195	pathogenic	not provided	2019-12-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the ALDH3A2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 21872273). ClinVar contains an entry for this variant (Variation ID: 189163). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 21872273). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169590	SCV001527248	pathogenic	Sjögren-Larsson syndrome	2018-09-21	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].