Submissions for variant NM_000382.3(ALDH3A2):c.1157A>G (p.Asn386Ser)

gnomAD frequency: 0.00001  dbSNP: rs72547575

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000001711	SCV000798553	likely pathogenic	Sjögren-Larsson syndrome	2018-03-13	criteria provided, single submitter	clinical testing
Invitae	RCV000793431	SCV000932783	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 386 of the ALDH3A2 protein (p.Asn386Ser). This variant is present in population databases (rs72547575, gnomAD 0.03%). This missense change has been observed in individual(s) with ALDH3A2-related conditions (PMID: 10792573, 21531120, 23450279, 29071827, 29159939). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALDH3A2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001711	SCV002598616	pathogenic	Sjögren-Larsson syndrome	2022-09-22	criteria provided, single submitter	clinical testing	Variant summary: ALDH3A2 c.1157A>G (p.Asn386Ser) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251468 control chromosomes. c.1157A>G has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (example, Aoki_2000, Nakajima_2011, Takeichi_2013, Dong_2020, Cheng_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and reported a reduction in alcohol dehydrogenase activity in the skin of a homozygous affected patient, however, as primary data supporting this finding are not presented, this report does not allow convincing conclusions about the variant effect (Aoki_2000). Three 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000001711	SCV000021867	pathogenic	Sjögren-Larsson syndrome	2000-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001711	SCV001463377	pathogenic	Sjögren-Larsson syndrome	2020-09-16	no assertion criteria provided	clinical testing